Genetics of Colorectal Cancer (PDQ®)–Health Professional Version
Attenuated Familial Adenomatous Polyposis (AFAP)
AFAP is a heterogeneous clinical entity characterized by fewer adenomatous polyps in the colon and rectum than in classic FAP. It was first described clinically in 1990 in a large kindred with a variable number of adenomas. The average number of adenomas in this kindred was 30, though they ranged in number from a few to hundreds.[192] Adenomas in AFAP are believed to form in the mid-twenties to late twenties.[68] Similar to classic FAP, the risk of CRC is higher in individuals with AFAP; the average age at diagnosis, however, is older than classic FAP at 56 years.[30,31,193] Extracolonic manifestations similar to those in classic FAP also occur in AFAP. These manifestations include upper GI polyps (FGPs, duodenal adenomas, and duodenal adenocarcinoma), osteomas, epidermoid cysts, and desmoid tumors.[68]
AFAP is associated with particular subsets of APC pathogenic variants, including missense changes. Three groups of site-specific APC pathogenic variants causing AFAP have been characterized:[30-33,194,195]
- Pathogenic variants associated with the 5’ end of APC and exon 4 in which patients can manifest 2 to more than 500 adenomas, including the classic FAP phenotype and upper GI polyps.
- Exon 9–associated phenotypes in which patients may have 1 to 150 adenomas but no upper GI manifestations.
- 3’ region pathogenic variants in which patients have very few adenomas (<50).
APC gene testing is an important component of the evaluation of patients suspected of having AFAP.[196] It has been recommended that the management of AFAP patients include colonoscopy rather than flexible sigmoidoscopy because the adenomas can be predominantly right-sided.[196] The role for and timing of risk-reducing colectomy in AFAP is controversial.[197] If germline APC pathogenic variant testing is negative in suspected AFAP individuals, genetic testing for MUTYH pathogenic variants may be warranted.[137]
Patients found to have an unusually or unacceptably high adenoma count at an age-appropriate colonoscopy pose a differential diagnostic challenge.[198,199] In the absence of family history of similarly affected relatives, the differential diagnosis may include AFAP (including MAP), Lynch syndrome, or an otherwise unclassified sporadic or genetic problem. A careful family history may implicate AFAP or Lynch syndrome.
Table 8 summarizes the clinical practice guidelines from different professional societies regarding surveillance of AFAP.
MUTYH-Associated Polyposis (MAP)
MAP is an autosomal recessively inherited polyposis syndrome caused by pathogenic variants in the Mut Y homolog gene. The Mut Y homolog gene, which is known as MUTYH, was initially called MYH, but was subsequently corrected because the myosin heavy chain gene already had that designation. MUTYH is located on chromosome 1p34.3-32.1.[201] The protein encoded by MUTYH is a base excision repair glycosylase, which repairs one of the most common forms of oxidative damage. Over one hundred unique sequence variants of MUTYH have been reported (Leiden Open Variation Database). A founder pathogenic variant with ethnic differentiation is assumed for MUTYH pathogenic variants. In white populations of northern European descent, two major variants, Y179C and G396D (formerly known as Y165C and G382D), account for 70% of biallelic pathogenic variants in MAP patients; 90% of these patients carry at least one of these pathogenic variants.[202] Other causative variants that have been found include P405L (formerly known as P391L) (Netherlands),[203,204] E480X (India),[205] Y104X (Pakistan),[206] 1395delGGA (Italy),[207,208] 1186-1187insGG (Portugal),[209] and p.A359V (Japan and Korea).[210-212]
The MUTYH gene was first linked to polyposis in 2002 in three siblings with multiple colonic adenomas and CRC but no APC pathogenic variant.[142] MAP has a broad clinical spectrum. Most often it resembles the clinical picture of AFAP, but it has been reported in individuals with phenotypic resemblance to classical FAP and Lynch syndrome.[213] MAP patients tend to develop fewer adenomas at a later age than patients with APC pathogenic variants [140,214] but still carry a high risk of CRC (35%–75%).[7,215,216] A 2012 study of colorectal adenoma burden in 7,225 individuals reported a prevalence of biallelic MUTYH pathogenic variants of 4% (95% CI, 3%–5%) among those with 10 to 19 adenomas, 7% (95% CI, 6%–8%) among those with 20 to 99 adenomas, and 7% (95% CI, 6%–8%) among those with 100 to 999 adenomas.[217] This broad clinical presentation results from the MUTYH gene's ability to cause disease in its homozygous or compound heterozygous forms. Based on studies from multiple FAP registries, approximately 7% to 19% of patients with a FAP phenotype and without a detectable APC germline pathogenic variant carry biallelic variants in the MUTYH gene.[7,140,205,218]
Adenomas, serrated adenomas, and hyperplastic polyps can be seen in MAP patients.[219] The CRCs tend to be right-sided and synchronous at presentation and seem to carry a better prognosis than sporadic CRC.[201] Clinical management guidelines for MAP range between once a year to every 3 years for colonoscopic surveillance beginning at age 18 to 30 years,[95,200,215] with upper endoscopic surveillance beginning at age 25 to 30 years.[200] (Refer to Table 9 for more information about available clinical practice guidelines for colon surveillance in MAP patients.) The recommended upper endoscopic surveillance interval can be based on the burden of involvement according to Spigelman criteria.[200] Total colectomy with ileorectal anastomosis or subtotal colectomy may be necessary for patients with MUTYH-associated polyposis depending on overall polyp burden.[215,220]
Although MAP is the only known biallelic (recessive) adenoma cancer predisposition syndrome described to date, there are examples of biallelic cases presenting with childhood tumors in which MMR genes are involved. (Refer to the Biallelic mismatch repair deficiency section in the Lynch syndrome section of this summary for more information.)
Table 9 summarizes the clinical practice guidelines from different professional societies regarding colon surveillance of biallelic MAP.
Many extracolonic cancers have been reported in patients with MAP including gastric, small intestinal, endometrial, liver, ovarian, bladder, thyroid, and skin cancers (melanoma, squamous epithelial, and basal cell carcinomas).[221,222] Additionally, noncancerous extracolonic manifestations have been reported in a few MAP patients including lipomas, congenital hypertrophy of the retinal pigment epithelium, osteomas, and desmoid tumors.[140,207,222,223] Female MAP patients have an increased risk of breast cancer.[224] These extracolonic manifestations seem to occur less frequently in MAP than in FAP, AFAP, or Lynch syndrome.[225,226]
Duodenal polyps in MAP
Similar to FAP, individuals with MAP often develop duodenal adenomas, and are at risk of developing duodenal cancer. Given the relatively recent identification of MAP compared with FAP, the incidence of duodenal polyps and risk of duodenal cancer in MAP is less well defined. Small case series have suggested the incidence of duodenal polyps in MAP to be approximately 30%, considerably lower than that of FAP. In a registry-based study the prevalence of duodenal polyps was 17%; however, only 50% of individuals in this study had undergone an upper GI endoscopy, suggesting the incidence of duodenal polyps was likely underestimated. The lifetime risk of duodenal cancer was estimated to be 4%.[222]
A registry study from the United Kingdom and the Netherlands explored incidence of duodenal polyps and duodenal cancer in a group of patients with MAP who were undergoing regular duodenal surveillance.[227] Of 92 patients, 31 (34%) had evidence of duodenal polyps. The median age at duodenal adenoma detection was 50 years, and in 65% of patients duodenal adenomas were diagnosed at baseline endoscopy. Eighty-four percent of patients had Spiegelman stage I or stage II polyposis at first detection of polyps, with no patients with stage IV polyposis and no high-grade dysplasia detected. In subsequent surveillance only two patients progressed to Spiegelman stage IV polyposis, after 3.6 and 7.0 years, respectively. There additionally appeared to be sparing of the ampulla, with only two individuals having diminutive polyps without dysplasia in the ampulla. No cancers were detected in patients enrolled in upper GI surveillance programs within these registries. Two individuals with MAP were diagnosed with ampullary and duodenal cancer respectively at ages 83 and 63 years at the time of first-ever upper GI endoscopies. Therefore, duodenal polyps appear less prevalent in MAP compared with FAP, and appear at a later age. On the basis of these results, the authors suggest upper GI endoscopic screening in MAP be initiated at age 35 years.
Because MAP has an autosomal recessive inheritance pattern, siblings of an affected patient have a 25% chance of also carrying biallelic MUTYH pathogenic variants and should be offered genetic testing. Similarly, testing can be offered to the partner of an affected patient so that the risk in their children can be assessed.
The clinical phenotype of monoallelic MUTYH pathogenic variants is less well characterized with respect to incidence and associated clinical phenotypes, and its role in susceptibility to polyposis and colorectal carcinoma remains unclear. Approximately 1% to 2% of the general population carry a pathogenic variant in MUTYH.[7,140,142] A 2011 meta-analysis found that carriers of monoallelic MUTYH pathogenic variants are at modestly increased risk of CRC (odds ratio [OR], 1.15; 95% CI, 0.98–1.36); however, given the rarity of carriers of monoallelic pathogenic variants, they account for only a trivial proportion of all CRC cases.[228] A large study of 2,332 heterozygotes among 9,504 relatives of 264 CRC cases with a MUTYH pathogenic variant found that the risk of CRC at age 70 years was 7.2% for men and 5.6% for women, irrespective of family history. Among those with an FDR with a CRC diagnosis before age 50 years, the risk at age 70 years was 12.5% for men and 10% for women.[216] Caution should be exercised in the interpretation of this study as the vast majority of carrier status from this study was imputed and not based on genotype. The authors felt the risk for MUTYH heterozygotes with an FDR with CRC was sufficiently high to warrant more intensive surveillance than the general population (but the same as for anyone with an FDR with CRC diagnosed before age 50 y).[214,216]
MMR genes may interact with MUTYH and increase the risk of CRC. An association between MUTYH and MSH6 has been reported. Both proteins interact together in base excision repair processes. A study reported a significant increase of MSH6 pathogenic variants in carriers of monoallelic MUTYH pathogenic variants with CRC compared with noncarriers with CRC (11.5% vs. 0%; P = .037).[229] However, a German study failed to duplicate these findings.[230] Additionally, a larger study found no increased cancer risk for carriers of MMR pathogenic variants with a MUTYH variant compared with those with a MMR pathogenic variant alone.[231]
NTHL1
A study utilizing whole-exome sequencing in 51 individuals with multiple colonic adenomas from 48 families identified a homozygous germline nonsense pathogenic variant in seven affected individuals from three unrelated families in the base-excision repair gene NTHL1.[232] These individuals had CRC, multiple adenomas (8–50), none of which were either hyperplastic or serrated, and in three affected females, there was either endometrial cancer or endometrial complex hyperplasia. There were two other individuals who developed duodenal adenomas and duodenal cancer. All pedigrees were consistent with autosomal recessive inheritance. Upon examining three cancers and five adenomas from different affected individuals, none showed microsatellite instability (MSI). These neoplasms did show enrichment of cytosine to thymine transitions. Additional studies are needed to further define the phenotype. A subsequent study of 863 families with CRC and 1,600 families without CRC confirmed an association between NTHL1 pathogenic variants and inherited CRC risk.[233]
Oligopolyposis
Oligopolyposis is a popular term used to describe the clinical presentation of a polyp count or burden that is greater than anticipated in the course of screening in average-risk patients but that falls short of the requirement for a diagnosis of FAP. Thus, oligo-, Greek for few, can mean different things to different observers. While conceding a lack of consensus on the matter, the National Comprehensive Cancer Network (NCCN) committee on CRC screening suggests an AFAP diagnosis is worth considering when 10 to less than 100 adenomas are present.[95] It will be used here to describe the circumstance in which the polyp count (generally adenoma) is large enough, with or without any attendant family history, to raise in the mind of the endoscopist the possibility of an inherited susceptibility.
In the setting of known or suspected Lynch syndrome, the detection of one to ten adenomas is still in keeping with the diagnosis. A similar adenoma count in a young patient undergoing colonoscopy for symptoms or in a screening patient over age 50 years could raise the question of Lynch syndrome. In the appropriate clinical setting—early onset and positive family history—the detection of any number of adenomas may support the testing and diagnosis of a patient for underlying Lynch syndrome pathogenic variants, consistent with guidelines such as those offered by the NCCN. Some controversy exists over the utility of testing adenoma tissue for MSI, as the yield is lower than in invasive cancer.[234] In general, and subject to the above caveats, Lynch syndrome is not routinely considered in a discussion of oligopolyposis.
One study considered a series of polyps (37 adenomas) from 21 patients with known MMR pathogenic variants, performing MSI and immunohistochemistry (IHC) for MMR protein expression.[235] Overall, MSI-high (MSI-H) was seen in 41% and in 100% of adenomas larger than 1 cm. Adenomas measuring smaller than 1 cm yielded MSI about 30% of the time. Correlation between MSI and loss of staining on IHC was fairly high, although the discordance rate (17%) was higher than in other series that evaluated invasive cancers from known carriers of MMR pathogenic variants. A higher MSI likelihood was observed in subjects older than 50 years. IHC staining in relation to gene showed 8 of 12 MLH1adenomas to have lost protein expression, with 10 of 20 adenomas from MSH2 patients to have loss of expression. In contrast, none (0 of 6) of the adenomas from carriers of MSH6pathogenic variants had loss of associated protein expression. The authors concluded that while normal MSI/IHC was simply not informative, abnormal MSI/IHC was as likely in larger (>8 mm) polyps as in cancers and thus a reasonable test to consider.
AFAP is found at the other end of the oligopolyposis spectrum. Most cases will have more than 100 adenomas, albeit at a later age and often with a predominance of microadenomas of the right colon and with fewer, larger polyps in the left colon. Cases with a positive family history and an APC pathogenic variant are clearly variant cases of FAP, as the term AFAP implies.[236] However, patients with no immediate family history and a lesser adenoma burden may not be found to have an APC pathogenic variant. The lower the polyp count the lower the probability of having an APC pathogenic variant. Some of these cases are now known to carry biallelic MUTYH pathogenic variants, although even here, the lower the adenoma count the lower the variant likelihood.[237]
Another study evaluated 152 patients with 3 to 100 adenomas and another 107 APCpathogenic variant–negative patients with a “classic” FAP polyp burden for evidence of MUTYH pathogenic variants.[140] Six patients with multiple adenomas and eight with a classic FAP burden had biallelic MUTYH pathogenic variants. The authors concluded that a cut-point of about 15 adenomas was a threshold above which MUTYH testing was reasonable, and many insurance companies in the United States have adopted a policy based on this cumulative adenoma count. Similar rates for MUTYH biallelic pathogenic variants were found by others using 20 adenomas as the threshold for considering testing.[237]
Pathogenic variants in related DNA polymerase genes POLE and POLD1 have been described in families with oligopolyposis and endometrial cancer.[238,239] An elegant approach was employed using whole-genome sequencing in 15 selected patients with more than ten adenomas before age 60 years. Several had a close relative with at least five adenomas who could also have whole-genome sequencing performed. All tested patients had CRC or a first-degree relative (FDR) with CRC. All had negative APC, MUTYH, and MMR gene pathogenic variant test results. No variants were found to be in common among the evaluated families. In one family, however, linkage had established shared regions, in which one shared variant was found (POLE p.Leu424Val; c.1270C>G), with a predicted major derangement in protein structure and function. In a validation phase, nearly 4,000 affected cases enriched for the presence of multiple adenomas were tested for this variant and compared with nearly 7,000 controls. In this exercise, 12 additional unrelated cases were found to have the L424V variant, with none of the controls having the variant. In the affected families, inheritance of multiple-adenoma risk appeared to be autosomal dominant. Somatic variants in tumors were generally consistent with the otherwise typical chromosome instability pathway, as opposed to MSI or CpG island methylator phenotype (CIMP). No extracolonic manifestations were seen.
A similar approach, whole-genome testing for shared variants, with further “filtering” by linkage analysis identified a variant in the POLD1 gene (p.Ser478Asn; c.1433G>A). This S478N variant was identified in two of the originally evaluated families, suggesting evidence of common ancestry. The validation exercise showed one patient with polyps with the variant but no controls with the variant. Somatic variant patterns were similar to the POLE variant. Several cases of early-onset endometrial cancer were seen. The mechanism underlying adenoma and carcinoma formation resulting from the POLE L424V variant appeared to be a decrease in the fidelity of replication-associated polymerase proofreading. This in turn appeared to lead to variants related to base substitution. A subsequent study confirmed that POLE pathogenic variants are a rare cause of oligopolyposis and early-onset CRC.[240] All individuals in this study were negative for germline pathogenic variants in APC, MUTYH, and the MMR genes. The POLE variant L424V was found in 3 of 485 index cases with colorectal polyposis and early-onset CRC. Tumors were MSI and deficient of one or more MMR proteins in two of three index cases. Somatic variants in MMR genes, possibly the result of hypermutability secondary to POLE deficiency, were detected in these two cases.
The study authors recommend consideration of POLE and POLD1 testing in patients with multiple or large adenomas in whom alternative pathogenic variant testing is uninformative and surveillance akin to that afforded patients with Lynch syndrome or MAP.[238,239] POLE and POLD1 pathogenic variant testing is being incorporated into the new multiple-gene (panel) tests for CRC susceptibility offered commercially.
A majority of patients with oligopolyposis involving adenomas are currently not found to have an underlying predisposition when evaluated for pathogenic variants in known predisposition genes. Such cases are generally managed as if they are at an increased risk of recurrent adenomas even when the colon can be “cleared” of polyps endoscopically.
Oligopolyposis caused by juvenile polyposis syndrome (JPS) or PJS can be distinguished from adenomatous polyposis on simple endoscopic and histologic grounds. Serrated polyposis can present in highly variable fashion. The World Health Organization (WHO) criteria for serrated polyposis (=5 serrated polyps proximal to sigmoid with 2 =1 cm, or any number of polyps proximal to sigmoid if there is a relative with serrated polyposis, or >20 serrated polyps anywhere in the colon) have never been validated. Furthermore, no genetic basis has been established, even in the uncommon familial cases. But cases of oligopolyposis of the serrated variety can initially be challenging to distinguish from oligoadenomatosis, particularly when there is an admixture of adenomas. Consequently, such patients are increasingly being referred for genetic counseling and for consideration of genetic testing. Occasional cases of MUTYH biallelic pathogenic variants have been found in patients with at least some features of serrated polyposis and serrated polyps can be seen in Lynch syndrome. Generally though, the genetic workup of serrated polyposis is unrewarding.[241-245]
Hereditary mixed polyposis, characterized by histology that often includes adenomatous and hyperplastic polyps, has been associated with GREM1 pathogenic variants in a small number of Ashkenazi Jewish families. Polyp number in this syndrome is highly variable but is often in the spectrum consistent with oligopolyposis. (Refer to the Hereditary mixed polyposis syndrome section of this summary for more information.)
Lynch Syndrome
Introduction
Lynch syndrome is the most common inherited CRC syndrome and accounts for approximately 3% of all newly diagnosed cases of CRC. It is an autosomal dominant condition caused by pathogenic variants in the MMR genes MLH1 (mutL homolog 1), MSH2(mutS homolog 2), MSH6 (mutS homolog 6), and PMS2 (postmeiotic segregation 2), as well as the gene EPCAM (epithelial cellular adhesion molecule, formerly known as TACSTD1), in which deletions in EPCAM cause epigenetic silencing of MSH2. Lynch syndrome is also associated with a predisposition for developing several extracolonic manifestations, including sebaceous adenomas and cancers of the endometrium and ovaries, stomach, small intestine, transitional cell carcinoma of the ureters and renal pelvis, hepatobiliary system, pancreas, and brain. Lynch syndrome–associated cancers exhibit MSI; therefore, tumor testing is a key component in the diagnosis of Lynch syndrome, in addition to family history. Universal tumor testing of all CRCs is now recommended as a strategy to screen for Lynch syndrome and identify those individuals who may subsequently benefit from germline genetic testing. Intensive cancer screening and surveillance strategies, including frequent colonoscopy, along with risk-reducing surgeries, are mainstays in patients with Lynch syndrome.
History of Lynch syndrome
Between 1913 and 1993, numerous case reports of families with apparent increases in CRC were reported. As series of such reports accumulated, certain characteristic clinical features emerged: early age at onset of CRC; high risk of synchronous (and metachronous) colorectal tumors; preferential involvement of the right colon; improved clinical outcome; and a range of associated extracolonic sites including the endometrium, ovaries, other sites in the GI tract, uroepithelium, brain, and skin (sebaceous tumors). Terms such as cancer family syndrome, and hereditary nonpolyposis colorectal cancer (HNPCC) were used to describe this entity.[246]
The term Lynch syndrome replaced HNPCC and is applied to cases in which the genetic basis can be confidently linked to a germline pathogenic variant in a DNA MMR gene. Moreover, HNPCC is misleading as many patients have polyps and many have tumors other than CRC.
With the increased recognition of families that were considered to have a genetic predisposition to the development of CRC, research for a causative etiology led to the development of the Amsterdam criteria in 1990.[247] The Amsterdam criteria were originally used for the identification of high-risk families and included fulfillment of all of the following: three or more cases of CRC over two or more generations, with at least one diagnosed before age 50 years, and no evidence of FAP.
In 1987, a chromosomal deletion of a small segment of 5q led to the detection of a genetic linkage between FAP and this genomic region,[248] from which the APC gene was eventually cloned in 1991.[249] This led to searches for similar linkage in families suspected of having Lynch syndrome who had multiple cases of CRC inherited in an autosomal dominant fashion and young onset of cancer development. The APC gene was one of several genes (along with DCC and MCC) evaluated in families that fulfilled Amsterdam criteria, but no linkage was found among the Lynch kindreds. In 1993, an extended genome-wide search resulted in the recognition of a candidate chromosome 2 susceptibility locus in large families. Once MSH2, the first Lynch syndrome–associated gene, was sequenced, it was evident from the somatic variant patterns in the CRC tumors that the MMR family of genes was likely involved. Additional MMR genes were subsequently linked to Lynch syndrome, including MLH1, MSH6, and PMS2. Lynch syndrome now refers to the genetic disorder caused by a germline variant in one of these DNA MMR genes, distinguishing it from other familial clusters of CRC.
In 2009, a germline deletion in the EPCAM gene was identified as another cause of MSH2inactivation in the absence of a germline pathogenic variant in MSH2. The variant in EPCAMled to hypermethylation of the MSH2 promoter. Thus, EPCAM, which is not a DNA MMR gene, is also implicated in Lynch syndrome and is now routinely tested in at-risk patients along with the DNA MMR genes listed above.
Defining Lynch syndrome families
Families with a preponderance of CRC and a possible genetic predisposition were initially categorized as having Lynch syndrome based on family history criteria, as well as personal history of young-onset CRC. With the advent of molecular tumor diagnostic testing and the discovery of the germline alterations associated with Lynch syndrome, the clinical criteria have currently fallen out of favor due to their underperformance. However, their use, or the risk estimates provided by the Lynch syndrome prediction models, may be applicable among individuals without personal history of cancer but with a family history suggestive of Lynch syndrome, or for those individuals with CRC but without available tumor for molecular diagnostic testing. (Refer to the Universal tumor testing to screen for Lynch syndrome and the Clinical risk assessment models that predict the likelihood of an MMR gene pathogenic variant sections of this summary for more information.)
The first criteria for defining Lynch syndrome families were established by the International Collaborative Group meeting in Amsterdam in 1990 and are known as the Amsterdam criteria.[247] These research criteria were limited to diagnoses of familial CRC. In 1999, the Amsterdam criteria were revised to include some extracolonic cancers, predominantly endometrial cancer.[250] These criteria provide a general approach to identifying Lynch syndrome families, but they are not considered comprehensive; nearly half of families meeting the Amsterdam criteria do not have detectable pathogenic variants.[251]
Amsterdam criteria I (1990):
- One family member diagnosed with CRC before age 50 years.
- Two affected generations.
- Three affected relatives, one of them an FDR of the other two.
- FAP should be excluded.
- Tumors should be verified by pathological examination.
Amsterdam criteria II (1999):
- Same as Amsterdam criteria I, but tumors of the endometrium, small bowel, ureter, or renal pelvis can be used to substitute an otherwise qualifying CRC.
These criteria were subsequently used beyond research purposes to identify potential candidates for microsatellite and germline testing. However, the Amsterdam criteria failed to identify a substantial proportion of Lynch syndrome kindreds; families that fulfilled Amsterdam criteria I but did not have evidence of MSI and were without a pathogenic germline variant in a DNA MMR gene, were referred to as familial colorectal cancer type X (FCCX). (Refer to the FCCX section of this summary for more information.)
With the hallmark feature of MSI associated with Lynch syndrome tumors, and the limitations of the Amsterdam criteria related to low sensitivity, the Bethesda guidelines were introduced in 1997. The Bethesda guidelines are a combination of clinical, histopathologic, and family cancer history features that identify cases of CRC that warrant MSI tumor screening. The Bethesda guidelines (with a subsequent revision in 2004) were formulated to target patients in whom evaluation of CRC tumors for MMR deficiency should be considered, and to improve the sensitivity of clinical criteria used to identify individuals who are candidates for mutational DNA analysis.[252,253] (Refer to the Genetic and molecular testing for Lynch syndrome section of this summary for more information about testing for MSI and IHC.)
Bethesda guidelines (1997):
- Cancer in families that meet the Amsterdam criteria.
- The presence of two Lynch syndrome–related cancers, including synchronous and metachronous CRCs or associated extracolonic cancers. [Note: Endometrial, ovarian, gastric, hepatobiliary, or small-bowel cancer or transitional cell carcinoma of the renal pelvis or ureter.]
- The presence of CRC and a FDR with CRC and/or Lynch syndrome–related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed before age 45 years, and the adenoma diagnosed before age 40 years.
- CRC or endometrial cancer diagnosed before age 45 years.
- Right-sided CRC with an undifferentiated pattern (solid/cribriform) on histopathology diagnosed before age 45 years. [Note: Solid/cribriform defined as poorly differentiated or undifferentiated carcinoma composed of irregular, solid sheets of large eosinophilic cells and containing small gland-like spaces.]
- Signet-ring–cell CRC diagnosed before age 45 years. [Note: Composed of more than 50% signet ring cells.]
- Adenomas diagnosed before age 40 years.
Revised Bethesda guidelines (2004)*:
- CRC diagnosed in an individual younger than 50 years.
- Presence of synchronous, metachronous colorectal, or other Lynch syndrome–associated tumors.**
- CRC with MSI-H pathologic associated features diagnosed in an individual younger than 60 years. [Note: Presence of tumor-infiltrating lymphocytes, Crohn-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.]
- CRC or Lynch syndrome–associated tumor** diagnosed in at least one FDR younger than 50 years.
- CRC or Lynch syndrome–associated tumor** diagnosed at any age in two FDRs or second-degree relatives.
*One criterion must be met for the tumor to be considered for MSI testing.
**Lynch syndrome–associated tumors include colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, biliary tract, and brain tumors; sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome; and carcinoma of the small bowel.[253,254]
Although the Bethesda guidelines were able to identify a higher proportion of Lynch syndrome carriers than the Amsterdam criteria, they still missed approximately 30% of Lynch syndrome families.[255] Furthermore, the Bethesda guidelines were not consistently used in clinical practice to identify the subset of individuals with CRC who should have MSI tumor testing; the guidelines were deemed cumbersome and difficult to remember by health care providers and the opportunity to refer for genetic evaluation was missed.[256]
With the advent of alternative approaches, including universal testing of all newly diagnosed cases of CRC for MSI (regardless of age at diagnosis or family history of cancer), clinical criteria for Lynch syndrome have been rendered obsolete. While the Bethesda guidelines were intended for individuals with cancer, their performance in individuals unaffected by cancer may still be of use. Given the limited modalities available to assess unaffected individuals for Lynch syndrome, family history and the use of clinical criteria may be appropriate in identifying those who warrant further genetic evaluation and testing.
Clinical risk assessment models that predict the likelihood of an MMR gene pathogenic variant
Because health care providers ineffectively use clinical criteria to select individuals with CRC for genetic referral and evaluation for Lynch syndrome, computer-based clinical prediction models were developed and introduced in 2006 as alternative modalities to provide systematic genetic risk assessment for Lynch syndrome. The risk models include the PREMM (PREdiction Model for gene Mutations) models, MMRpredict, and MMRpro.[257-260]
Three models (PREMM[1,2,6], MMRpredict, and MMRpro) quantify an individual’s probability of carrying an MMR gene variant in MLH1, MSH2, and MSH6. The PREMM(1,2,6) model was subsequently extended to include prediction of pathogenic PMS2 and EPCAMvariants and is the only model to provide prediction of all five genes associated with Lynch syndrome (PREMM5).[260]
While the models were all created for the same purpose, they differ in the way they were developed and the variables used to predict risk. In addition, the populations in which they were validated reveal each model’s specific characteristics that may impact accuracy.[261-270] Deciding on which model to use in the risk assessment process depends on both the clinical setting in which it is applied and the patient population that is being evaluated. MMRpro’s predictions account for family size and unaffected relatives, the possibility of including molecular tumor data in the risk analysis, and the option of predicting pathogenic variant carrier status following germline testing. The major limitation in the widespread use of MMRpro in routine practice is the need to input data from the entire pedigree (including individuals without cancer), which is relatively time-consuming. Its best use is likely to be as a genetic counseling tool in a specialized high-risk clinic or research setting, as its accessibility is also limited. PREMM’s major advantages include that it is easy to use, available as an online tool, and has been extensively validated, including in a self-administered setting in a gastrointestinal clinic.[271] It includes risk prediction based on personal and family cancer history up to second-degree relatives for a broad spectrum of extracolonic cancers. However, the model does not take into account family size and may overestimate the likelihood of a pathogenic variant in a pedigree that includes multiple elderly family members who are unaffected by CRC or endometrial cancer. Given the ease with which one can use the PREMM model (it has been deemed less time-consuming than MMRpro in validation studies),[266] it may be used by diverse health care providers whose primary aim is to identify patients who should be referred for genetic evaluation, and is likely to be most useful in the pretesting decision-making process. Lastly, MMRpredict’s use may be limited overall because of its less accurate risk estimates [272] when used to evaluate families with Lynch syndrome–associated cancers and older individuals affected by CRC; the model was developed using data from young-onset CRC cases (patients diagnosed at age <55 y) and did not include extracolonic malignancies. Furthermore, the model does not incorporate tumor testing results or provide post-hoc risk estimates based on gene sequencing results.
Overall, there is ample evidence that each of the models has superior performance characteristics of sensitivity, specificity, and positive and negative predictive values that support their use when compared with the existing clinical guidelines for diagnosis and evaluation of Lynch syndrome. Because of the diverse clinical settings in which a health care provider has the opportunity to assess an individual for Lynch syndrome, prediction models offer a potentially feasible and useful strategy to systematically identify at-risk individuals, whether or not they are affected with CRC.
Summary
In conclusion, the presence of tumor MSI in CRCs, along with a compelling personal and family history of cancer, warrants germline genetic testing for Lynch syndrome, and most clinical practice guidelines provide for such an approach. These guidelines combine genetic counseling and testing strategies with clinical screening and treatment measures. Providers and patients alike can use these guidelines to better understand available options and key decisions. (Refer to Table 14 for more information about practice guidelines for diagnosis and colon surveillance in Lynch syndrome.)
Genetics of Lynch syndrome
The genetics of both the tumor and the germline have an important role in the development and diagnosis of Lynch syndrome. Tumor DNA in Lynch syndrome–associated tumors exhibits characteristic MSI, and in these cases, there is typically loss of IHC expression for one or more of the proteins associated with the MMR genes. Molecular testing with MSI and/or IHC has been adopted as a universal screen for diagnosis of Lynch syndrome in newly diagnosed patients with CRC and endometrial cancer. IHC testing results can potentially direct gene-specific germline testing. Many genetic testing laboratories offer multigene (panel) tests that simultaneously test for pathogenic variants in all of the Lynch syndrome–associated genes (and often additional genes associated with inherited cancer susceptibility).
Genetic and molecular testing for Lynch syndrome
MSI
The presence of MSI in colorectal tumor specimens is a hallmark feature of Lynch syndrome and can be cause for suspicion of a germline pathogenic MMR gene variant. Microsatellites are short, repetitive sequences of DNA (mononucleotides, dinucleotides, trinucleotides, or tetranucleotides) located throughout the genome, primarily in intronic or intergenic sequences.[273,274] The term MSI is used when colorectal, endometrial, or metastatic tumor DNA [275] shows insertions or deletions in microsatellite regions when compared with normal tissue. MSI indicates probable defects in MMR genes, which may be due to somatic variants, germline variants, or epigenetic alterations.[276] In most instances, MSI is associated with absence of protein expression of one or more of the MMR proteins (MSH2, MLH1, MSH6, and PMS2). However, loss of protein expression may not be seen in all tumors with MSI and not all tumors with loss of protein expression on IHC will be microsatellite unstable.
Certain histopathologic features are strongly suggestive of MSI phenotype, including the presence of tumor-infiltrating lymphocytes (refer to Figure 4), Crohn-like reaction, mucinous histology, absence of dirty necrosis, and histologic heterogeneity.[277]
Initial designation of a colorectal adenocarcinoma as microsatellite unstable was based on the detection of a specified percentage of unstable loci from a panel of three dinucleotide and two mononucleotide repeats that were selected at a National Institutes of Health (NIH) Consensus Conference and referred to as the Bethesda panel. If more than 30% of a tumor's markers were unstable, it was scored as MSI-H; if at least one, but fewer than 30% of markers were unstable, the tumor was designated MSI-low (MSI-L). If no loci were unstable, the tumor was designated microsatellite stable (MSS). Most tumors arising in the setting of Lynch syndrome will be MSI-H.[278] The clinical relevance of MSI-L tumors remains controversial; the probability is very small that these tumors are associated with a germline pathogenic variant in an MMR gene.
The original Bethesda panel has been replaced by a pentaplex panel of five mononucleotide repeats,[278] which has improved the detection of MSI-H tumors.
(Refer to the Prognostic and therapeutic implications of MSI section of this summary for more information about the treatment implications of MSI testing.)
(Refer to the Universal tumor testing to screen for Lynch syndrome section of this summary for information about the utilization of MSI status in the diagnostic workup of a patient with suspected Lynch syndrome.)
IHC
IHC methods are cheaper, easier to understand, and more widely available as a surrogate for MSI and, for these reasons, have replaced polymerase chain reaction (PCR)–based MSI testing in most institutions. IHC is performed in the colorectal or endometrial tumor (or metastatic sites) [275] for protein expression using monoclonal antibodies for the MLH1, MSH2, MSH6, and PMS2 proteins. Isolated loss of expression of any one of these proteins may suggest which specific MMR gene is altered in a particular patient.[279-282] However, certain proteins can form heterodimers (or have other binding partners) and yield loss of two proteins expressed on IHC.
MSI can lead to nucleotide-pairing slippage (looping) in which single nucleotide mispairs are introduced. Heterodimers of MMR proteins are formed to identify the errors and bind the DNA at these sites.[276,283] For example, MSH2 protein complexes with MSH6 protein to form MutSα, which has the main ability to repair single base pair mismatches and single base pair loop-out lesions that can occur during the replication of a mononucleotide repeat sequence. In the absence of MSH6 protein, the MSH2 protein will dimerize with the MSH3 protein forming the MutSβ complex, which has the ability to trigger repair of larger loop-out DNA mismatches, but also has some overlapping activity to repair lesions usually repaired by MutSα.
As a result, when the germline pathogenic variant is in the MSH2 gene, the tumor IHC may not express both MSH2 and MSH6, as the latter protein requires binding to MSH2 for stability. In this case, if no pathogenic variant is found in either gene, germline pathogenic variant testing for EPCAM should be considered if it was not already included. Approximately 20% of patients with absence of MSH2 and MSH6 protein expression by IHC and no MSH2 or MSH6 pathogenic variant identified will have germline deletions in EPCAM.[284] The latter mechanism accounts for approximately 5% of all Lynch syndrome cases.[284] A deletion in one allele of exon 9 of the EPCAM (TACSTD1) gene, which is immediately upstream of the start site of MSH2 and in the same orientation, can lead to transcriptionalread-through and methylation of the MSH2 promoter, and subsequent silencing of MSH2 in any tissue that expresses EPCAM. The presence of EPCAM pathogenic variants showing similar methylation-mediated MSH2 loss has been reported in numerous families.[285] On the strength of these observations, germline EPCAM testing is performed in patients with loss of MSH2 protein expression on IHC testing of their CRCs but who lack a detectable MSH2 germline pathogenic variant and is included with MSH2 testing in all colon cancer gene panels.
In patients with no variants in any of these genes, tumor sequencing may reveal double somatic MSH2 variants. (Refer to the EPCAM and Lynch-like or HNPCC-like syndromesections of this summary for more information.)
Similarly, the loss of MLH1 (either by germline pathogenic variant or hypermethylation of the MLH1 promoter) results in the absence of expression of both MLH1 and PMS2 proteins in the tumor. The most common abnormal IHC pattern for DNA MMR proteins in colorectal adenocarcinomas is loss of expression of MLH1 and PMS2. PMS2 and MLH1 function as a stable heterodimer known as MutLα. MutLα binds to MutSβ and guides excision repair of the newly synthesized DNA strand.[276] A functional defect in MLH1 results in degradation of both MLH1 and PMS2, while a defect in PMS2 negatively affects only PMS2 expression. Thus, a loss of MLH1 and PMS2 indicates an alteration in MLH1 (promoter hypermethylation or germline variant), while loss of PMS2 expression indicates a germline PMS2 variant. However, among 88 individuals with PMS2-deficient CRC, PMS2 germline pathogenic variant testing followed by MLH1 germline pathogenic variant testing revealed pathogenic PMS2 variants in 49 individuals (74%) and MLH1 pathogenic variants in 8 individuals (12%).[286] Eighty-three percent of the alterations in MLH1 were missense variants, but two relatives carried identical MLH1 variants, and one individual, who developed two tumors with retained MLH1 expression, carried an intronic variant that led to skipping of exon 8.[286] Therefore, in CRCs with solitary loss of PMS2 expression, an MLH1 germline pathogenic variant should be sought if no PMS2 germline variant is found. Tumors with MSI and loss of MSH2 and MSH6 protein expression are generally indicative of an underlying MSH2 germline variant (inferred MSH2 pathogenic variant). Unlike the case with MLH1, MSI with MSH2 loss is rarely associated with somatic hypermethylation of the promoter.
Unlike MLH1 and MSH2 (which both dimerize with other proteins or have other binding partners), germline pathogenic variants in MSH6 and PMS2 result in the isolated loss of those specific proteins by IHC. However, tumors from MSH6 pathogenic variant carriers may not display the MSI phenotype at a frequency as high as MLH1 and MSH2 carriers (despite an inactive DNA MMR system), as there are pathogenic missense variants that do not completely abrogate protein expression yielding false negative results by IHC testing.[265,287] In a study that reported tumor testing results among MMR germline carriers enrolled through the Colon Cancer Family Registry, 7 of 24 carriers (28%) with MSH6pathogenic variants had tumors that displayed normal protein expression on IHC staining. IHC tumor testing was more informative for MLH1 and MSH2 pathogenic variant carriers in which 93% of MLH1 carriers had correlating loss of MLH1 protein expression and 96% of MSH2 carriers had loss of MSH2 protein expression.[265]
In some cases, tumors manifest MSI and/or IHC shows loss of DNA MMR protein expression, but no germline pathogenic variant is identified. This condition is known as Lynch-like (or HNPCC-like) syndrome and the tumor phenotype is predominantly due to biallelic somatic inactivation of DNA MMR genes and not a pathogenic germline alteration. (Refer to the Lynch syndrome–related syndromes section of this summary for more information.)
Somatic MLH1 hypermethylation
It is important to recognize that hypermethylation of the MLH1 promoter, a somatic event confined to the tumor, can lead to abnormal protein expression of MLH1 on IHC. Approximately 10% to 15% of sporadic CRC cases have a microsatellite unstable tumor phenotype due to MLH1 hypermethylation and are not heritable. These sporadic MSI colon cancers [288] have a generalized excess of DNA methylation referred to as CIMP.[289] (Refer to the CIMP and the serrated polyposis pathway section in the Introduction section of this summary for more information.) Because loss of MLH1 protein expression on IHC occurs in both Lynch syndrome and sporadic tumors, its specificity for predicting germline MMR gene variants is lower than for the other MMR proteins, and additional molecular testing is often necessary to clarify the etiology of MLH1 absence.
BRAF pathogenic variants have been detected in 68% of CRC tumors with MLH1 promoter hypermethylation and very rarely, if ever, in CRC from patients with Lynch syndrome.[290-293] This suggests that detection of somatic BRAF V600E pathogenic variant detection in CRC may be useful in excluding individuals from germline variant testing. As a result, BRAFV600 testing and/or MLH1 hypermethylation assays are increasingly utilized in universal Lynch syndrome–testing algorithms in an attempt to distinguish between an absence of MLH1 protein expression caused by hypermethylation and germline MLH1 pathogenic variants. Making such a distinction is also a more cost-effective approach in excluding individuals from germline testing.
Biallelic mismatch repair deficiency (BMMRD)
Rarely, patients with MMR gene variants carry such variants in both parental alleles. When two variant alleles are identified, whether homozygous or compound heterozygous, this is termed biallelic mismatch repair deficiency (BMMRD) or constitutional mismatch repair deficiency (CMMRD). The likelihood of BMMRD involving homozygous MMR gene pathogenic variants will inevitably be higher among consanguineous unions. The incidence of consanguinity may be higher in rural and otherwise geographically and/or culturally isolated populations.[294]
Tumor studies yield characteristic abnormalities. In a series of 28 patients with BMMRD,[295] 17 brain tumors showed loss of staining for the MMR protein in the normal stromal cells in addition to neoplastic cells, showing a contradistinction from tumors in patients with Lynch syndrome in which normal staining is retained in nontumor cells. In contrast to this characteristic feature seen with IHC, PCR-based MSI analysis was not reliable, as 20 of 28 tumors were MSS. Of the tumors that were MSI-H, essentially all were colon cancers.
The PMS2 gene is markedly overrepresented in cases of BMMRD. It has been suggested that the presence of homozygosity of variants in the other MMR genes is a prenatally lethal state, while the otherwise milder expression of PMS2 is consistent with survival when present in both parental alleles.
(Refer to the BMMRD section in the Prevalence, clinical manifestations, and cancer risks associated with Lynch syndrome section for more information about the clinical phenotype of BMMRD.)
Constitutional epimutation
While somatic hypermethylation of the MLH1 promoter is acquired and not uncommon, examples of MLH1 promoter hypermethylation have been described in the germline and are generally not associated with a stable Mendelian inheritance. This constitutional methylation of MMR genes occurs most often in MLH1 and, to a lesser extent, MSH2 and is termed constitutional epimutation .[297] A constitutional epimutation (also referred to as a primary epimutation) is an acquired alteration in normal tissue that silences an active gene or activates an inactive gene.[298] Such epimutations occur most often in maternal alleles. In some cases all somatic cells appear involved, while in others there is evidence of mosaicism. Tumors in patients with primary epimutations are generally indistinguishable from those otherwise typical of Lynch syndrome germline variant carriers, including age at onset, tumor spectrum, and presence of abnormal MSI and IHC. Since these are not inherited in a Mendelian fashion, antecedent family history of tumors is minimal, and risk to offspring somewhat unpredictable. Epimutations present in a de novo case seem to typically be "erased" in the process of gametogenesis and to not be passed to the next generation. Very rare cases of inherited MLH1 epimutations have been reported.[299,300]
Interpreting molecular alterations in tumors and distinguishing the likely primary epimutation cases from those of sporadic MSI poses significant challenges. Most instances of absence of MLH1 expression are caused by the sporadic hypermethylation of the MLH1promoter. Rare instances of a de novo constitutional epimutation in MLH1 [301] or an inherited germline MLH1 methylation [302] add some complexity to the interpretation of MSI associated with absence of MLH1 expression. Akin to sporadic MSI, primary epimutation tumors show methylation of the MLH1 promotor and may show BRAF variants as well. As noted above, family history of cancer in such cases tends to be minimal or absent, as in true sporadic MSI. Distinguishing such cases from sporadic cases may call for assaying normal tissue (e.g., blood or normal colon mucosa) for evidence of MLH1methylation, which will be absent from true sporadic cases and absent from carriers of conventional Lynch syndrome MMR pathogenic variants.
Such MLH1-predominant primary epimutations are to be distinguished from secondary epimutations such as those occurring when MSH2 is methylated as a consequence of inherited variants in the upstream EPCAM gene. (Refer to the EPCAM section of this summary for more information.)
Molecular diagnostic tumor testing to screen for Lynch syndrome in clinical practice
While many molecular pathology laboratories can assess both MSI and IHC, an approach that uses IHC testing as the initial screen for defective MMR activity has been favored because it is less labor intensive and more cost-effective.[303,304] Part of this rationale is that the information provided by IHC may target germline genetic testing toward one specific MMR gene (with the exception of loss of MLH1 expression) as opposed to a comprehensive testing strategy of all Lynch syndrome–related MMR genes that would be directed by the use of MSI alone.[255,303,305-308] While MSI testing was originally favored in the oncologic evaluation of individuals with CRC for its prognostic and therapeutic implications, screening for Lynch syndrome can be more effectively directed by IHC testing.
Universal tumor testing to screen for Lynch syndrome
Use of MSI and/or IHC testing in all newly diagnosed cases of CRC, regardless of the age at diagnosis or family history of cancer, increases the sensitivity of the initial screen for Lynch syndrome, especially for carriers of MSH6 and PMS2 pathogenic variants. This approach is more sensitive than existing clinical criteria, as many individuals with Lynch syndrome are diagnosed at older ages (>50 y) and have less striking family histories of CRC than previously appreciated. This universal testing of colorectal (and endometrial) tumors using either MSI or IHC testing has been recommended by many professional organizations and is being widely adopted.[309,95,310-312]
Genetic risk assessment and MMR gene variant testing in individuals with newly diagnosed CRC can lead to improved outcomes for the patient and at-risk family members. Dating back to 2009, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP), a project developed by the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC), reported that there was sufficient evidence to recommend offering tumor screening for Lynch syndrome to individuals with newly diagnosed CRC to reduce morbidity and mortality in relatives.[313,314] At that time, there was insufficient evidence to recommend a specific testing strategy between MSI and IHC.
Several studies have demonstrated the feasibility of universal screening for Lynch syndrome. Initial experience from one institution found that among 1,566 patients screened using MSI and IHC, 44 patients (2.8%) had Lynch syndrome. For each proband, an average of three additional family members were subsequently diagnosed with Lynch syndrome.[255] A subsequent pooled analysis of 10,206 incident CRC patients tested with MSI/IHC as part of four large studies revealed a pathogenic variant detection rate of 3.1%.[315] This study compared four strategies for tumor testing for the diagnosis of Lynch syndrome: (1) testing all individuals meeting at least one criterion of the Bethesda guidelines; (2) testing all individuals meeting Jerusalem recommendations;[316] (3) testing all individuals with CRC aged 70 years or younger, or older than 70 and meeting at least one criterion of the Bethesda guidelines; and (4) universal testing of all individuals with CRC.[315] Tumor testing with MSI involved panels individualized at each institution and IHC involved testing all four of the DNA MMR genes involved with Lynch syndrome, across all institutions. The strategy of tumor testing in all individuals diagnosed with CRC at age 70 years or younger and testing individuals over age 70 who met one of the revised Bethesda guidelines yielded a sensitivity of 95.1%, a specificity of 95.5%, and a diagnostic yield of 2.1%. This strategy missed 4.9% of Lynch syndrome cases, but 34.8% fewer cases required IHC/MSI testing, and 28.6% fewer cases underwent germline testing than in the universal approach.
The consideration to further stratify the recommendation for molecular tumor testing by age (i.e., 70 y) warrants attention as it influences the cost-effectiveness of universal screening strategy.
Loss of MLH1 and PMS2 due to somatic hypermethylation is not uncommon, and is more frequently detected with increasing age at CRC diagnosis.[317] Therefore, additional molecular tumor testing including BRAF and MLH1 hypermethylation testing is recommended in cases in which there is loss of MLH1 and PMS2 expression on IHC, thereby decreasing the number of individuals referred for unnecessary germline genetic testing. A testing strategy including MLH1 hypermethylation analyses in individuals aged 70 years or younger with CRC who had loss of MLH1 on IHC was shown to be cost-effective in a population-based study of 1,117 individuals.[318]
Screening individuals with CRC for Lynch syndrome is most often performed in a stepwise fashion based on IHC tumor testing results that evaluate protein expression for the four MMR genes related to Lynch syndrome. One proposed strategy is summarized in Figure 6. This framework does not incorporate a germline testing approach that simultaneously evaluates multiple cancer susceptibility genes (multigene [panel] testing), which may be useful in select patient populations. (Refer to the Multigene [panel] testing section of this summary for more information.)
Cost-effectiveness of universal tumor screening for Lynch syndrome
Results are available from a Markov model that incorporated the risks of colorectal, endometrial, and ovarian cancers to estimate the effectiveness and cost-effectiveness of strategies to identify Lynch syndrome among persons aged 70 years or younger with newly diagnosed CRC .[304] The strategies incorporated in the model were based on clinical criteria, prediction algorithms, and tumor testing or up-front germline pathogenic variant testing followed by directed screening and risk-reducing surgery. IHC followed by BRAFpathogenic variant testing was the preferred strategy in this study. An incremental cost-effectiveness ratio of $36,200 per life-year gained resulted from this strategy. In this model, the number of relatives tested (3–4) per proband was a critical determinant of both effectiveness and cost-effectiveness. These results were similar to earlier analyses conducted by EGAPP which found that the most cost-effective approach was to test all tumors for absence of protein expression of MSH2, MLH1, MSH6, and PMS2 followed by targeted germline testing of MSH2, MLH1, or MSH6 offered depending on which protein was absent. If there was absence of MLH1, testing was offered for BRAF variant-negative tumors.[314]
NCCN 2018 guidelines support universal screening of all CRCs with IHC and/or MSI.[95] Universal screening in all individuals irrespective of age was associated with a doubling of incremental cost per life-year saved compared with screening only those younger than 70 years.[304] The authors of this analysis conclude that screening individuals younger than 70 years appears reasonable, while screening all individuals regardless of age might also be acceptable, depending on willingness to pay.
However, it is important to note that the conclusions from this study were contingent upon the number of at-risk relatives who underwent germline testing (through a process known as cascade screening ) based on the identification of a germline MMR gene variant in the index case of CRC in the family. In their model, to meet the accepted $50,000 cost-effective threshold, testing a minimum of three to four relatives was necessary.[304] This emphasizes the importance of provider-to-patient communication, family communication, and the need to ensure improved uptake of germline testing in Lynch syndrome families with a known causative gene. (Refer to the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for more information about family communication and uptake of genetic testing in families with Lynch syndrome.)
Another study addressed the cost-effectiveness of testing for pathogenic variants in the Lynch syndrome–associated genes and evaluated 21 screening strategies, including clinical criteria, use of clinical Lynch syndrome prediction models, and molecular tumor testing.[319] The model included two steps: (1) measurement of the newly identified number of Lynch syndrome diagnoses; and (2) measurement of the life-years gained as a result of confirming Lynch syndrome in a healthy carrier. Among all of the strategies modeled, screening the proband with a predictive model such as PREMM(1,2,6) followed by IHC for MMR protein expression and germline genetic testing was the best approach, with an incremental cost-effectiveness ratio of $35,143 per life-year gained. Germline genetic testing on all probands was the most effective approach, but at a cost of $996,878 per life-year gained. The authors concluded that the initial step of Lynch syndrome screening should utilize a predictive model in the proband, and that both universal testing and general population screening strategies were not cost-effective screening strategies for Lynch syndrome.
Establishment of an upper age limit for universal tumor testing remains controversial. Some experts have endorsed testing only individuals with CRC who are younger than 70 years (reserving testing in individuals ≥70 y for only those meeting the revised Bethesda criteria; with this strategy, 5% of carriers would be missed).[320] However, others have advocated against an upper age limit for testing given the potential benefit to younger generations via cascade screening and the opportunity for increased surveillance and other prophylactic interventions in individuals found to carry a known familial pathogenic variant.
Another cost-effectiveness analysis was performed using data from 179 consecutive endometrial cancer patients diagnosed at or before age 70 years and screened with MMR IHC and reflex MLH1 promoter hypermethylation, among whom seven Lynch syndrome carriers (3.9%) were identified.[321] Only one of the seven Lynch syndrome probands was age 50 years or younger at endometrial cancer diagnosis. The authors calculated that screening women diagnosed with endometrial cancer at age 51 to 70 years resulted in an additional 29.3 life-years gained (on top of the 45.4 life-years gained by screening women diagnosed at age ≤50 y), and the incremental cost-effectiveness ratio for screening all diagnoses at age 70 years or younger versus diagnoses at age 50 years or younger was 5,252 euro per life-year gained. Universal tumor-based screening of all women age 70 years or younger was also cost-effective, compared with strategies using the Bethesda guidelines to guide MMR and MSI testing with an incremental cost-effectiveness ratio of 6,668 euro per life-year gained.
The cost-effectiveness of universal tumor testing in both CRC and endometrial cancer is largely driven by the assumption of cascade screening through which other at-risk family members will be identified, tested, and subsequently pursue their own cancer risk reduction.[304]
The cost of germline genetic testing continues to decrease with advancements in DNA mutational analyses, including simultaneous testing of multiple germline variants associated with malignancy, through multigene (panel) tests. As a result, additional cost-effective analyses using more updated data related to germline testing will need to be conducted. Multigene (panel) testing may become a more favorable and cost-effective approach in the future.
Considerations and limitations related to universal tumor testing for Lynch syndrome
While universal screening continues to be adopted nationally, there is significant variability in the uptake and approach to molecular testing. A 2011 survey of the National Society of Genetic Counselors revealed that more than 25% of respondents had some form of universal screening implemented at their center. Tumor screening methods varied; 34 (64.2%) of 53 centers started with IHC, 11 (20.8%) of 53 centers started with MSI testing, and 8 (15.1%) of 53 centers performed both tests on newly diagnosed colorectal tumors.[322] A 2012 survey suggested that some form of universal screening was being routinely performed at 71% of the National Cancer Institute (NCI) Comprehensive Cancer Centers, but utilization dropped to 15% among a random sample of community hospital cancer programs.[323]
Because adherence to universal screening for Lynch syndrome may be poor (many patients are not referred for genetic evaluation and testing), a prospective quality improvement study utilizing the Six Sigma conceptual framework was conducted to improve the implementation of universal genetic screening among young patients with CRC.[324] The main aim of the study was to increase the proportion of tumor studies for deficient MMR among patients with early-onset CRC (aged 18–50 y). The intervention involved patient and provider education, in addition to visual cues provided at point of care. The study demonstrated an improvement of 21.5% in the rate of IHC testing in young adults with CRC over the 12-month postintervention period compared with the preintervention period.
Studies reporting uptake of genetic testing for Lynch syndrome have largely focused on individuals and families who were selected for potential risk of Lynch syndrome based on family history or clinical characteristics. While universal tumor screening is increasingly being adopted to identify newly diagnosed patients who may have a germline variant, few studies have examined the uptake of genetic testing after universal tumor testing. An important implication of universal screening for Lynch syndrome is that it does not result in automatic germline testing in appropriate individuals. In the clinical setting, more follow-up by health care teams to facilitate referral to genetic counseling for patients with abnormal tumor screening results may improve completion of genetic testing.[325] Higher levels of patient completion of genetic testing after abnormal tumor screening may be associated with having genetic counselors involved in this process to disclose screen-positive results, provide counseling after tumor testing, or facilitate referrals.[326]
Subsequent genetic counseling requires coordination between the pathologist, the referring surgeon or oncologist, and a cancer genetics service. As an illustration, a population-based screening study found that only 54% of patients with an IHC-deficient tumor (that was BRAF pathogenic variant–negative) ultimately consented to and proceeded with germline MMR testing.[327] One institution found 21 pathogenic variants among 1,100 patients who underwent routine MSI and IHC testing after a diagnosis of CRC. This study found markedly increased uptake of genetic counseling and germline MMR gene testing when both the surgeon and a genetic counselor received a copy of abnormal MSI/IHC results, especially when the genetic counselor played an active role in patient follow-up.[325]
In contrast to tumor testing, which is commonly performed without a patient's prior knowledge, germline genetic testing, such as germline testing for MMR pathogenic variants, generally includes genetic counseling and requires patient permission before it is performed. A cross-sectional survey of U.S. cancer programs (20 NCI–designated Comprehensive Cancer Centers and 49 community hospital cancer programs) found that, of those that performed MSI and/or IHC testing as part of standard pathologic evaluation at the time of colon cancer diagnosis in all or select cases, none required written informed consent before tumor testing.[323]
Diagnostic strategies for all individuals diagnosed with endometrial cancer
Given the increased prevalence of endometrial cancer among carriers of MMR pathogenic variants, there is a growing consensus to screen patients with endometrial cancer for Lynch syndrome.
In a study that examined the feasibility and desirability of performing tumor screening of all endometrial cancers, regardless of age at diagnosis or family history of cancer, at least 2.3% (95% CI, 1.3%–4.0%) of newly diagnosed patients had Lynch syndrome.[328,329] Eight of thirteen cases diagnosed with Lynch syndrome were aged 50 years or older, eight did not meet published family history criteria for Lynch syndrome, and two would have been missed by MSI testing. Because of the increased prevalence of endometrial cancer and the results of this study, the authors support universal screening of endometrial cancers for Lynch syndrome. (Refer to the IHC section of this summary for more information about performing IHC for MMR protein expression.)
Another smaller study of 242 consecutive endometrial cases demonstrated a 4.5% (11/242) prevalence of MMR-deficient cases lacking somatic MLH1 promoter hypermethylation, including four cases (1.7%) with germline MMR mutations, four cases (1.7%) with two somatic MMR alterations on next-generation sequencing, and two cases (0.8%) with otherwise unexplained MMR-deficiency.[330] Such findings demonstrate that universal MMR tumor screening of endometrial cancers will identify individuals with underlying Lynch syndrome and a spectrum of non-Lynch syndrome cases with various forms of MMR-deficiency.
Another study prospectively evaluated universal IHC-based screening of both CRC and endometrial cancer cases, irrespective of age at diagnosis.[331] In both the tertiary and community settings, 1,290 CRC and 484 endometrial cancer cases were screened between 2011 and 2013. The study additionally calculated PREMM(1,2,6) and PREMM5 scores for all patients in whom a germline pathogenic variant was detected. Abnormal staining was observed in 22% of endometrial cancers and 18.8% of CRCs. After excluding those cases felt to be sporadic because of the presence of BRAF and/or hypermethylation of MLH1, 10.8 % of patients with CRC and 6.6% of patients with endometrial cancer were referred for genetic counselling. Lynch syndrome was diagnosed in 24 individuals (1.4%), 66% of whom had CRC. The overall detection rate of Lynch syndrome was 1.7% in endometrial cancer cases and 1.2% in CRC cases. Among Amsterdam criteria, Bethesda guidelines, PREMM(1,2,6), and PREMM5, the best performing model was PREMM5, which would have detected 82% of cases identified by universal screening.
The cost-effectiveness of tumor testing of women diagnosed with endometrial cancer was examined in a model-based simulation study and included IHC testing in the following scenarios: (1) diagnosis before age 50 years; (2) diagnosis before age 60 years; (3) any age at diagnosis with the presence of an FDR with any Lynch syndrome–associated cancer; and (4) all cases irrespective of diagnosis age and family history. Women fulfilling Amsterdam II criteria or those diagnosed before age 50 years with at least one FDR with any Lynch syndrome–associated cancer were directly referred for genetic counseling and genetic testing without IHC testing. A strategy of IHC testing for MMR protein expression in all patients with endometrial cancer and an FDR with any Lynch syndrome–associated cancer was reported to be cost-effective in the detection of Lynch syndrome.[332] This strategy had an incremental cost ratio of $9,126 per life-year gained relative to the least-costly strategy, which was genetic testing on all women diagnosed with endometrial cancer before age 50 years with at least one FDR with a Lynch syndrome–related cancer. Life expectancy was highest with the most inclusive testing strategy of IHC testing of all women with endometrial cancer irrespective of age at diagnosis or family history, but had the least favorable incremental cost ratio of $648,494 per life-year gained. NCCN recommends tumor testing with IHC and/or MSI, Lynch syndrome–specific genetic testing for MMR genes and EPCAM, or multigene (panel) testing of all endometrial cancers.[95] Despite these recommendations, the uptake of universal screening in women newly diagnosed with endometrial cancer is unclear.
(Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about endometrial cancer as a component of Lynch syndrome.)
Germline genetic testing
Genetic testing for germline pathogenic variants in MLH1, MSH2, MSH6, PMS2, and EPCAMcan help formulate appropriate intervention strategies for the affected variant-positive individual and at-risk family members, many of whom may be unaffected by cancer.
If a pathogenic variant is identified in an affected person, then testing for that same pathogenic variant should be offered to all at-risk family members. At-risk relatives who test negative for the identified pathogenic variant in the family are not at increased risk of CRC or other Lynch syndrome–associated malignancies and can follow surveillance recommendations applicable to the general population. Family members who carry the familial pathogenic variant are referred to surveillance and management guidelines for Lynch syndrome. (Refer to the Management of Lynch syndrome section of this summary for more information.)
If no pathogenic variant is identified in the affected family member, then testing is considered negative for Lynch syndrome in that individual. With advances made in DNA sequencing technologies, it is unlikely that current gene testing is not sensitive enough to detect a pathogenic variant in the genes tested. Advances in testing, including the common use of next-generation sequencing (NGS) by most commercial testing laboratories have improved upon the detection of certain alterations such as large deletions or genomic rearrangements as well as the presence of a pseudogene PMSCL in PMS2.
Possible reasons why a pathogenic variant may not be detected include the following:
- The family could have a variant in a yet-unidentified gene that causes Lynch syndrome or a predisposition to colon cancer.
- The individual tested in the family may have developed colon cancer through a nongenetic mechanism (i.e., it is a sporadic case also known as a phenocopy), while the other cases in the family are really the result of a germline variant. If this scenario is suspected, testing another affected individual who has had a Lynch syndrome–associated cancer is recommended.
- In cases in which a CRC tumor displayed MSI and/or abnormal IHC but no germline pathogenic variant was detected, biallelic somatic variants may be the etiology. These cases have been coined Lynch-like and are not considered familial.
Failure to detect a pathogenic variant could mean that the family truly is not at genetic risk despite a clinical presentation that suggests a genetic basis (e.g., the patient may have double somatic variants in an MMR gene). If no variant can be identified in an affected family member, testing should not be offered to at-risk members because results would be uninformative for the relatives. They would remain at increased risk of CRC by virtue of their family history and should continue with recommended intensive screening.
(Refer to the Management of Lynch syndrome section of this summary for more information.)
Multigene (panel) testing
Germline mutation analysis of MLH1, MSH2 (including EPCAM), MSH6, and PMS2 may be considered in instances in which tumor tissue is not available from individuals to test for MSI and/or MMR protein IHC. This approach has become less expensive with the advent of multigene (panel) testing, which is now offered by several clinical laboratories at a cost that may be comparable to single-gene testing. The cost of multigene testing may also approach the cost of tumor screening and may prove to be a cost-effective approach in individuals affected by CRC. At present, multigene tests are not routinely recommended for universal screening for Lynch syndrome among all newly diagnosed CRC patients, but they may be very useful in select populations, such as those with early-onset CRC [333] or from familial, high-risk clinic-based populations. It is also important to note that pathogenic variants may be detected in other cancer-associated genes beyond Lynch syndrome. In a study of 1,112 individuals who met NCCN criteria for Lynch syndrome testing and who underwent multigene testing with a 25-gene panel, as expected, 114 individuals (9.0%) were found to have pathogenic variants in MMR genes; however, 71 individuals (5.6%) were found to have a pathogenic variant in non-Lynch syndrome cancer predisposition genes, such as BRCA1, BRCA2, APC, MUTYH (biallelic), and STK11. Lastly, multigene tests yield a high proportion of VUS. In the aforementioned study, a total of 479 patients (38%) had one or more VUS.[334]
Individuals with early-onset CRC have been shown to have a high frequency and wide spectrum of germline pathogenic variants, indicating that panel testing in this population may be beneficial. In a study of 450 patients with early-onset CRC (mean age at diagnosis, 42.5 y) and a family history including at least one FDR with colon, endometrial, breast, ovarian, and/or pancreatic cancer, 75 germline pathogenic or likely pathogenic variants were identified in 72 patients (16%).[333] The spectrum of variants identified included Lynch syndrome and non-Lynch syndrome–associated genes, including several genes that have not traditionally been associated with CRC (e.g., BRCA1/BRCA2, ATM, CHEK2, PALB2, and CDKN2A). Given the high frequency and variety of hereditary cancer syndromes identified, the authors suggested that multigene testing in this population may be warranted.
Multigene testing has also been examined in a larger study of 1,058 individuals with CRC who were unselected for age at diagnosis, personal or family history, or MSI/MMR test results.[335] Germline pathogenic variants in cancer susceptibility genes were identified in 105 individuals (9.9%). While 33 individuals (3.1%) carried pathogenic variants in Lynch syndrome genes, 74 (7.0%) had pathogenic variants in non-Lynch syndrome–associated genes, including APC, MUTYH, BRCA1/BRCA2, PALB2, CDKN2A, TP53, and CHEK2. These data illustrate the breadth of variants that may be identified in unselected CRC patients; thus, use of a comprehensive multigene test may be warranted.
A 2017 study examined the frequency of pathogenic Lynch syndrome–associated gene variants in individuals undergoing multigene testing at a single commercial United States laboratory between 2012 and 2015, and reported on the characteristics of those carriers identified with Lynch syndrome.[336] The study reports on the largest cohort of individuals tested through multigene testing to date; data was reported on 34,980 individuals who had undergone various multigene panel tests that included the MMR and EPCAM genes, where the indication for testing was not limited to Lynch syndrome. A total of 618 pathogenic variants were identified in 612 individuals (1.7%) and analyses were conducted on 579 subjects (after exclusion of 33 individuals who had a Lynch syndrome–associated variant and a second MMR variant or other pathogenic alteration in another cancer predisposition gene). The majority of carriers were affected by cancer, including non-Lynch syndrome–associated malignancies, where breast cancer was most frequently reported (124/423, 23.5%). MSH6 variants were most prevalent (29.3%), followed by PMS2 (24.2%), MSH2(23.7%), MLH1 (21.6%), and EPCAM (1.2%). This finding differs from previous data where MSH2 and MLH1 variants were more prevalent, as individuals were more often selected for Lynch syndrome–specific testing due to a personal and/or family history of CRC.
The study reports on genotype-phenotype correlations on 528 Lynch syndrome carriers, the majority of whom had CRC (186, 35.2%) and endometrial cancer (136, 25.8%), followed by breast cancer (124, 23.5%) and ovarian cancer (74, 14%).[336] One hundred forty-five carriers presented with breast or ovarian cancer as their sentinel tumor and did not carry a prior diagnosis of CRC or endometrial cancer prior to the time of multigene testing. When examining MMR gene variant distribution among tumor-specific subgroups, a higher frequency of MSH6 and PMS2 variants were detected in carriers with breast cancer only than MLH1 and MSH2, where the latter pathogenic variants were more frequent in subjects with CRC only. For patients with breast cancer only, the frequency of PMS2 gene variants was significantly higher than population estimates, which was not the case for MLH1, MSH2, or MSH6. A comparable retrospective study reported similar findings. Standardized incidence ratios (SIRs) of breast cancer were calculated by comparing observed breast cancer frequencies in a population of 423 women with pathogenic or likely pathogenic variants in MMR genes with those in the general population. The authors reported a statistically significant age-standardized risk of breast cancer for MSH6 carriers (SIR = 2.11; 95% CI, 1.56–2.86) and PMS2 carriers (SIR = 2.92; 95% CI, 2.17–3.92).[337] A critical limitation of both of these studies was the excess of breast cancer cases in the overall referral population as well as the known high background population prevalence of MSH6 and PMS2 germline pathogenic variants.
Clinical criteria for the identification of Lynch syndrome, including the Amsterdam criteria, revised Bethesda guidelines, or the PREMM(1,2,6) risk prediction model, would have failed to identify 27.3% of Lynch syndrome carriers in this study.[336] Given the increased prevalence of breast and ovarian cancers, 58.9% met the NCCN guidelines for BRCA1/BRCA2testing and of these, 36.7% also met NCCN guidelines for Lynch syndrome testing. Lastly, there were limited data on tumor testing results, available only on 18.8% of pathogenic variant carriers, where results were often discordant with the altered gene, which was most often reported in MSH6 and PMS2 carriers. Results of this study support the use of multigene testing for Lynch syndrome and further study of the respective cancer risks, as current testing strategies limit identification of Lynch syndrome carriers and associated malignancies.
Lastly, germline MMR genes have been detected unexpectedly among individuals undergoing multigene testing for cancers not commonly associated with Lynch syndrome, such as breast and prostate cancer. As a result, the cancer spectrum associated with Lynch syndrome may be wider than previously appreciated. (Refer to the Breast cancer and Prostate cancer sections of this summary and the Genetics of Prostate Cancer summary for more information.)
(Refer to the Multigene [panel] testing section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about multigene testing, including genetic education and counseling considerations, and research examining the use of multigene testing.)
Cost-effectiveness of multigene (panel) testing
As genetic testing becomes routine rather than the exception, questions regarding the cost of testing are inevitable. Historically, a cost-effectiveness ratio of $50,000 per quality-adjusted life-year (QALY) has been utilized as the benchmark for good value for care.[338] Over time it has been suggested that this threshold is too low and that other thresholds such as $100,000 or $150,000 be utilized.[338]
A 2015 study evaluated the cost-effectiveness of multigene testing for CRC and polyposis syndromes in patients referred to a cancer genetics clinic.[339] These authors developed a decision model to estimate the immediate and downstream costs for patients referred for evaluation and of CRC surveillance in family members identified as carriers of pathogenic variants. The costs were estimated on the basis of published models from the CDC and from an academic molecular genetics laboratory. They classified the syndromes on the basis of inheritance pattern and penetrance of CRC. Four custom panels were compared with the standard of care. The four panels tested for (1) Lynch syndrome–associated genes only (MLH1, MSH2, MSH6, PMS2, and EPCAM); (2) genes in panel 1 and additional genes associated with autosomal dominant inheritance and high CRC penetrance (APC, BMPR1A, SMAD4, and STK11); (3) genes in panels 1 and 2 and those associated with autosomal recessive inheritance with high CRC penetrance (MUTYH); or (4) all genes in the first three panels and those associated with autosomal dominant conditions with low penetrance (PTEN, TP53, CDH1, GALNT12, POLE, POLD1, GREM1, AKT1, and PIK3CA). The respective costs were as follows: panel 1, $144,235 per QALY; panel 2, $37,467 per QALY; panel 3, $36,500 per QALY; and panel 4, $77,300 per QALY when compared with panel 3. The authors concluded that the use of an NGS multigene test that includes highly penetrant CRC and polyposis syndromes and Lynch syndrome cancer genes was the approach most likely to provide clinically meaningful results in a cost-effective fashion.
The cost of germline genetic testing continues to decrease with advancements in technology since the time this model analysis was conducted; additional studies are needed to continue to assess the cost-effectiveness of this testing approach.
Prevalence, clinical manifestations, and cancer risks associated with Lynch syndrome
Lynch syndrome is an autosomal dominant syndrome characterized by an early age of onset of CRC, excess synchronous and metachronous colorectal neoplasms, right-sided predominance, and extracolonic tumors, notably endometrial cancer. Lynch syndrome is caused by pathogenic variants in the DNA MMR genes, namely MLH1 (mutL homolog 1) on chromosome 3p21;[340,341] MSH2 (mutS homolog 2) on chromosome 2p22-21;[342,343]MSH6 on chromosome 2p16;[344] and PMS2 (postmeiotic segregation 2) on chromosome 7p22.[340-343,345-348] The function of these genes is to maintain the fidelity of DNA during replication. Lynch syndrome is also associated with pathogenic variants of the EPCAM (epithelial cellular adhesion molecule, formerly known as TACSTD1) gene on chromosome 2p21, which causes epigenetic silencing of MSH2, located immediately downstream of this gene.[349,350]
Lynch syndrome accounts for about 3% of all newly diagnosed cases of CRC.[303] In earlier studies, the average age at CRC diagnosis in carriers of Lynch syndrome pathogenic variants was reported as young as 44 to 52 years [255,303,351] versus 71 years in sporadic CRC.[352] In subsequent studies that corrected for ascertainment bias to determine cancer-related risk estimates and genotype-phenotype correlations, the average age at diagnosis of CRC was reported to be 61 years among carriers of Lynch syndrome–associated pathogenic variants.[353]
Original reports related to overall and gene-specific prevalence estimates in Lynch syndrome relied heavily on retrospective data from familial cancer registries worldwide. Earlier risk estimates of CRC (and endometrial cancer) reported in Lynch syndrome were subject to ascertainment bias and overestimation, given that data were derived largely from familial cancer registries and cases were often ascertained based on young-onset CRC or an increased number of CRC cases among relatives. Correction of these cancer risk estimates has been made possible through modified segregation analyses, where statistical methodology provides more accurate estimates and adjusts for ascertainment bias. Conversely, risk estimates related to extracolonic malignancies, with the exception of endometrial cancer, may be prone to underestimation because many families may have underreported these cancers in relatives, and Lynch syndrome–related tumors may have occurred later in life.
In a large population-based study of 5,744 CRC cases who were recruited irrespective of family cancer history from the United States, Australia, and Canada, it was estimated that 1 in 279 individuals in the population carry an MMR pathogenic variant associated with Lynch syndrome.[354]
In another population-based study of 450 individuals with CRC but limited to young onset with diagnoses occurring before age 50 years, germline pathogenic variants were identified in 72 of 450 individuals (16%), as detected by multigene (panel) testing for inherited cancer susceptibility genes. As expected, the majority of identified variants were in genes known to be associated with CRC, predominantly Lynch syndrome (37 of 72 patients, 51.4%). However, 13 of 72 patients (18.1%) had pathogenic variants in genes not traditionally associated with CRC, including but not limited to BRCA1/BRCA2, which accounted for 8% of the identified variants. Because of the high frequency and wide variety of pathogenic variants identified, the authors suggested consideration of multigene testing for all individuals with early-onset CRC.[333]
Gene-specific considerations and associated CRC risk
The MLH1 and MSH2 genes were originally thought to account for most pathogenic variants of the MMR genes found in Lynch syndrome. However, the prevalence of MSH6and PMS2 pathogenic variants has been increasing with improved DNA mutational analyses and universal tumor screening of all CRCs.[354] MSH6 and PMS2 variants may be more common in unselected cases of CRC (and endometrial cancer),[354] compared with MLH1 and MSH2 variants which were more commonly identified in individuals from high-risk CRC clinics.[355,356]
MLH1
In early studies, the prevalence of MLH1 pathogenic variants in individuals with Lynch syndrome was reported to be between 41.7% [357] and 50%,[358] making MLH1 the most commonly altered MMR gene in Lynch syndrome families. It was not until a report on the population-based prevalence of Lynch syndrome that the MLH1 pathogenic variant was estimated to be 1 in 1,946, ranking third after PMS2 (1 in 714) and MSH6 (1 in 758), as estimated in a large international study of 5,744 CRC cases.[354]
MLH1 pathogenic variants are associated with the entire spectrum of malignancies associated with Lynch syndrome [358] The lifetime risk of any Lynch syndrome–associated cancer by age 70 years has been found to range between 59% and 65% in MLH1 pathogenic variant carriers.[283] The highest risk among carriers of pathogenic MLH1 variants is for CRC, which is estimated to be between 41% and 68%,[3,4,353] and the mean age at diagnosis of CRC was 42.8 years (range, 16–81 y) in one study that included 137 affected individuals.[359] In a more recent prospective study using pooled European registry data of 944 MLH1 carriers without cancer, the cumulative CRC incidence was 46% at age 70 years, despite colonoscopic surveillance (albeit at various intervals).[5]
MSH2
The prevalence of MSH2 pathogenic variants in individuals or families with Lynch syndrome has varied across studies. MSH2 pathogenic variants were reported in 38% to 54% of Lynch syndrome families in studies including large cancer registries and among cohorts of early-onset CRC (younger than age 55 y).[257,360] The reported prevalence of MSH2 pathogenic variants was 32.8% in 2012 in the database of the International Society for Gastrointestinal Hereditary Tumors (InSiGHT), a large professional organization devoted to the collaborative study of familial GI cancer,[357] with families readily ascertained based on the presence of extracolonic cancers in MSH2-associated Lynch syndrome. However, the prevalence of MSH2 pathogenic variants was estimated to be 1 in 2,841 in a population-based cohort of 5,744 CRC cases recruited from the United States, Australia, and Canada;[354] MSH2 was the least prevalent of the MMR gene variants associated with Lynch syndrome.
The risk of any Lynch syndrome–associated cancer by age 70 years has been found to range between 57% to nearly 80% in MSH2 pathogenic variant carriers.[283] The lifetime risk of colon cancer associated with MSH2 pathogenic variants is estimated to be between 48% and 68%.[3,4,353] In a case series of Lynch syndrome patients, those carrying germline MSH2 pathogenic variants (49 individuals, 45% women) had a lifetime (cutoff age, 60 y) risk of extracolonic cancers of 48% compared with 11% for MLH1 carriers (56 individuals, 50% women).[361] In a more recent prospective study using pooled European registry data of 616 MSH2 carriers without cancer, the cumulative CRC incidence was 35% at age 70 years, despite colonoscopic surveillance.[5]
The mean age at diagnosis of CRC in MSH2 carriers has been comparable to MLH1 carriers. One study that included 143 affected individuals with MSH2 pathogenic variants found a mean age at CRC diagnosis of 43.9 years (range, 16–90 y). The same study reported a mean age at CRC diagnosis of 42.8 years (range, 16–81 y) in 137 MLH1 pathogenic variant carriers.[359]
MSH6
Most series have reported a prevalence of germline MSH6 pathogenic variants in approximately 10% of Lynch syndrome families from high-risk clinics and a higher proportion of unselected CRC patients, at approximately 50%.[344,362-367] The reported prevalence of MSH6 pathogenic variants in the InSiGHT database was 18% in 2012.[357] The wide range of prevalence estimates for pathogenic MSH6 variants was a result of small sample sizes, ascertainment bias, and the later age of CRC onset and less striking family histories in MSH6-associated Lynch syndrome families compared with MLH1- and MSH2-associated Lynch syndrome families.[362] This is in line with findings from a population-based study of 42 carriers of deleterious MSH6 germline pathogenic variants, 30 (71%) of whom had a family cancer history that did not meet the Amsterdam II criteria.[6] In a recent, international, population-based study of 5,744 CRC cases, the prevalence of MSH6pathogenic variants was estimated to be 1 in 758, ranking as the second most prevalent of the MMR genes following PMS2.[354]
The lifetime risk of any Lynch syndrome–associated cancer among MSH6 pathogenic variant carriers is approximately 25% [283] with CRC lifetime risk estimated to be between 12% and 22% [4,6] with MSH6 carriers diagnosed with CRC at a later age than MLH1 and MSH2 carriers. In an earlier study of 146 MSH6 carriers (59 men and 87 women) from 20 families, all of whom had truncating pathogenic variants in MSH6, there was a similar prevalence of CRC by age 70 years among MLH1, MSH2, and MSH6 carriers (P = .0854). However, the mean age at diagnosis for colorectal carcinoma was (a) 55 years for male MSH6 carriers (n = 21; range, 26–84 y) versus 43 years and 44 years in carriers of MLH1 and MSH2 pathogenic variants, respectively; and (b) 57 years for female MSH6 carriers (n = 15; range, 41–81 y) versus 43 years and 44 years in carriers of MLH1 and MSH2 pathogenic variants, respectively.[368]
The largest series of carriers of MSH6 pathogenic variants reported to date includes 113 families from five countries who were ascertained through family cancer clinics and population-based cancer registries.[6] Compared with the incidence for the general population, MSH6 pathogenic variant carriers had an eightfold increased incidence of CRC (hazard ratio [HR], 7.6; 95% CI, 5.4–10.8), which was independent of sex and age. By age 70 years, 22% (95% CI, 14%–32%) of male carriers of MSH6 pathogenic variants developed CRC compared with 10% (95% CI, 5%–17%) of female carriers. By age 80 years, the CRC prevalence doubled to 44% (95% CI, 28%–62%) of male carriers of MSH6 pathogenic variants diagnosed with CRC compared with 20% (95% CI, 11%–35%) among female carriers.
In a more recent prospective study using pooled European registry data of 305 MSH6carriers without cancer, the cumulative CRC incidence was 20% at age 70 years despite colonoscopic surveillance.[5]
PMS2
PMS2 was the last of the genes in the MMR family of genes to be identified. This was because lower penetrance among families made it more difficult to identify [369] using clinical criteria, and also because of limitations of DNA mutational analysis that result from pseudogene interference.
In earlier studies of individuals with CRC and suspected Lynch syndrome, the prevalence of PMS2 pathogenic variants was variable from 2.2% to 5%,[255,370] with an increase to 7.5% as reported in the InSiGHT database in 2012.[357] From a study examining universal tumor testing results from unselected cases of CRC in Switzerland, IHC evaluation of 1,000 consecutive cases found isolated absence of PMS2 expression in 1.5% of all tumors. If this frequency of PMS2-deficient CRCs were representative of all PMS2-associated Lynch syndrome, PMS2 would be the most common gene associated with Lynch syndrome.[371] Results from a large, population-based CRC cohort found that the prevalence of PMS2pathogenic variants was the highest among all MMR variants, in which 1 person in 714 carried a pathogenic PMS2 gene variant.[354]
The lifetime risk of any cancer has been found to range between 25% and 32% for heterozygous PMS2 pathogenic variant carriers.[283] A meta-analysis of three population-based studies and one clinic-based study estimated that for carriers of PMS2 pathogenic variants, the risk of CRC to age 70 years was 20% among men and 15% among women, and the risk of endometrial cancer was 15%.[372] Similarly, a European consortium of clinic-based registries, taking care to correct for ascertainment bias, found a cumulative lifetime (to age 70 y) CRC risk of only 19% in men and 11% in women with PMS2 pathogenic variants.[373] In addition, patients with PMS2 pathogenic variants presented with CRC 7 to 8 years later than did those with MLH1 and MSH2 pathogenic variants.[370] In a prospective study using pooled European registry data of 77 PMS2 carriers without cancer, the cumulative CRC incidence was 10% at age 70 years despite colonoscopic surveillance.[5] An analysis of nearly 5,000 patients from 284 PMS2 families from the European consortium, supplemented by data from two more registries, was intended to provide more robust PMS2-associated cancer risk estimates.[374] The risk of CRC up to age 80 years was 13% (95% CI, 7.9%–22%) for men and 12% (95% CI, 6.7%–21%) for women, compared with general population risk estimates of 6.6% and 4.7%, respectively. Endometrial cancer risk was found to be 13% (95% CI, 7%–24%). No excess risk of other Lynch syndrome–spectrum tumors was identified in these cohorts. The authors concluded that these data justify consideration of delaying initiation of colonoscopy until age 35 to 40 years, and with longer follow-up intervals (2–3 y), although this was not specifically studied. As with the original reports from the European Prospective Lynch Syndrome Database, it was not possible to assess the extent to which such colonoscopies and polypectomies might have reduced the rate of detected CRCs.
It is important to note that a more severe phenotype is seen among carriers of biallelic PMS2 pathogenic variants. (Refer to the BMMRD section in the Genetics of Lynch syndromesection of this summary for more information.)
The lifetime risk of CRC and endometrial cancer in carriers of these pathogenic variants is summarized in Table 12.
EPCAM
A subset of individuals with Lynch syndrome (approximately 1%) have a pathogenic variant in EPCAM, which leads to hypermethylation and inactivation of the MSH2 promoter.[375] In a European study of 194 EPCAM deletion carriers, the cumulative risk of CRC up to age 70 years was 75% with the average age at onset of 43 years. This is comparable to the risk in MSH2 carriers (up to 68% by age 70 y). However, the risk of endometrial cancer among women with an EPCAM deletion was only 12% in this study, compared with a risk of up to 71% in MSH2 carriers.[376] The associated phenotype is dependent on the location of the deletion variant in the 3’ end of the EPCAM gene; if the deletion is large and includes parts of the promoter of MSH2, the phenotype will be similar to other MSH2-associated Lynch syndrome families.[376] When the deletion involves the termination signal of EPCAM but spares all of the MSH2 gene and promoter, the phenotype is mainly confined to CRC.[377]
One study of two families with the same EPCAM deletion limited to the 3’ end of the gene and not extending into the promoter of MSH2 found few extracolonic cancers and no endometrial cancers.[377] However, a subsequent study demonstrated that women with MSH2 protein expression loss caused by EPCAM variants are also at risk of endometrial cancer.[376]
BMMRD
As described above, patients may carry MMR gene variants in both parental alleles, in a condition known as BMMRD. (Refer to the BMMRD section in the Genetics of Lynch syndrome section of this summary for more information.)
The occurrence of such biallelic variants is associated with a characteristic but not diagnostic clinical phenotype. Clinical features include hematologic malignancies and brain tumors in children. When GI tumors occur, the age of onset is strikingly low, sometimes before age 20 years. Café au lait spots and features otherwise suggesting neurofibromatosis are characteristic. Occasionally, patients present with multiple adenomas.
Ethnic variation and founder pathogenic variants in Lynch syndrome
The frequency of MMR variants does not differ markedly from population to population, with similar frequencies identified in a host of different countries. As with hereditary breast and ovarian cancer (HBOC), there are certain variants that occur at higher frequencies within a particular ethnic group. Notable in HBOC are the commonly recurring Ashkenazi Jewish variants, so common that direct-to-consumer testing is offered for these common variants. (Refer to the Population estimates of the likelihood of having a BRCA1 or BRCA2 pathogenic variant section in the PDQ summary on the Genetics of Breast and Gynecologic Cancers and the Direct-to-Consumer (DTC) Genetic Tests section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.) The ancientness of apparent founder variants is generally established by haplotype analysis. In some instances, what may appear to be a founder variant is simply a frequently recurring de novo variant.[378]
Among the first population findings regarding the MMR genes of Lynch syndrome was the recognition of two very common MLH1 variants in Finland, accounting for a majority of cases of Lynch syndrome in this country.[379,380] Since that time, founder variants have been identified in most populations in which relatively unselected series of patients with CRC have undergone variant testing. Many of the reports originate in Europe. As in Finland, these may be straightforward to identify in the setting of fairly homogeneous ethnicity with low immigration. Founder variants in Europe have been found in the United Kingdom, Sweden, Switzerland, Italy,[381] Portugal, France, Spain, and Hungary, and are likely present in all ethnic groups. Fewer such reports have come from Asia,[382] Latin America, the Middle East, and Africa.
In the United States, a deletion in exons 1–6 of the MSH2 gene has been estimated to account for as much as 20% of variants in that gene. This so-called American Founder Mutation has been determined by haplotype analysis to date back about 500 years.[383]
A South American study combining data from Uruguay, Colombia, Brazil, Argentina, and Chile also selected cases of interest according to Amsterdam and Bethesda features, yielding a 60% frequency of MLH1 and 40% frequency of MSH2. MSH6 and PMS2 were not evaluated. Selection bias likely influenced the frequency of variants and perhaps the relative contributions by MLH1 and MSH2. A possible founder variant in Colombia was noted.[384]
Although testing for commonly recurring founder variants in a given ethnic/geographic area has been considered to be a cost-effective first step when a step-wise strategy is employed, it is likely not necessary when the increasingly commonly approach of broad panel testing is undertaken as a basic strategy.
One consideration related to ethnicity is that of increased rates of consanguinity within certain populations and the subsequent risk of BMMRD. (Refer to the Biallelic mismatch repair deficiency [BMMRD] section of this summary for more information.)
Ethnic variation in the United States
In this section, the data exploring the distribution of MMR gene variants amongst differing ethnic groups in the United States are presented. The interpretation of these studies is challenging given the presence of selection and ascertainment bias. In addition, even population-based studies are limited by small sample sizes for many ethnic groups and self-reporting of ethnicity/race.
There are few data suggesting the presence of much variation in Lynch syndrome frequency according to geography or ethnicity. Within a small and/or homogeneous ethnic group the presence of founder variants may seem to increase the prevalence of variants in that particular gene. Slight differences in the proportion of MLH1 and MSH2 variants exist from one population to another. MSH6 and PMS2 have been insufficiently studied at the population level as to enable inferences about their relative frequencies.
The most representative population-based studies in the United States, such as that in Columbus, Ohio, have been overrepresented by whites, in accordance with their greater overall numbers. Consequently, data on minorities such as Hispanics and African Americans suffer from smaller and less rigorously representative samples.
A study conducted in Puerto Rico considered variants in 89 Caribbean Hispanic patients with Lynch syndrome suspected on the grounds of Amsterdam criteria or Bethesda guidelines.[385] Patients underwent either immediate germline testing or step-wise evaluation beginning with tumor MSI/IHC. Frequencies of variants by gene were 67% for MSH2, 25% for MLH1, and 8% for MSH6. No definite founder variants were evident. Clearly, the selection of participants according to clinical family history criteria would have led to an underreporting of the less penetrant MSH6 and PMS2 genes.
Clinic-based series from California, Texas, and Puerto Rico yielded an overall variant prevalence similar to those described, with somewhat more MLH1 than MSH2, but also including MSH6 and PMS2. Presence of potential founder variants traceable back to Spain and Europe were noted.[386]
The closest population-based information on Lynch syndrome in Hispanics is a Southern California study based on the California Tumor Registry, in which 265 patients were identified.[387] Of those with MSI-H tumors, 13 (62%) had MMR variants. Frequencies of MMR variants were 46% for MLH1 (6 of 13), 31% for MSH2 (4 of 13), 15% for MSH6 (2 of 13), and 8% for PMS2 (1 of 13).
The problem of small numbers is highlighted by the findings from the more truly population-based studies that have been done in the United States. In a study from Columbus, Ohio, only 8% of the consecutive series patients were African American and the proportion of Hispanics as a subset of whites was not stated.[333] In another study involving panel testing of nearly all CRC patients treated at Dana-Farber Cancer Institute, less than 5% were African American and less than 3% were Hispanic, underscoring the challenge of extracting meaningful data from small subsets.[334]
Lynch syndrome in African Americans
The issues in evaluating prevalence of Lynch syndrome and cancer risks associated with MMR variants in African Americans are similar to those in Hispanics: a heterogeneous population that has been understudied. A study of clinic-based data from 13 referral centers in the United States identified 51 families with Lynch syndrome with frequencies of MMR gene variants as follows: 61% MLH1, 21% MSH2, 6% MSH6, and 12% PMS2. Age of cancer onset distribution curves were very similar to those seen in white populations.[388] As with most of the studies in Hispanics, cases were not identified according to any consistent, programmatic evaluation such as universal tumor testing.
Risk of metachronous CRC
A hallmark feature of Lynch syndrome is that carriers of pathogenic MMR gene variants have an increased risk of development of synchronous and metachronous colorectal neoplasms. In one study of 382 individuals with Lynch syndrome from the Colon Cancer Family Registry, the incidence of metachronous CRCs was 16% at 10 years, 41% at 20 years, and 63% at 30 years after segmental colectomy.[389] The risk of metachronous CRC decreased in a stepwise fashion by 31% for every 10 cm of the colon that was removed, with none of the 50 individuals who had extensive colectomies diagnosed with metachronous CRC. Another prospective study of 1,273 patients with Lynch syndrome who had prior cancer reported a cumulative incidence of subsequent CRC of 46% for MLH1carriers, 48% for MSH2 carriers, and 23% for MSH6 carriers. This represents only a slightly greater risk of new cancers than pathogenic variant carriers with no previous cancer diagnosis. Excellent survival was again seen and was regarded as a combination of favorable tumor pathology and the effect of surveillance.[390]
Risk of extracolonic malignancies associated with Lynch syndrome
Patients with Lynch syndrome are at an increased risk of other cancers, especially those of the endometrium. The cumulative risk of extracolonic cancer has been estimated to be 20% by age 70 years in 1,018 women in 86 families, compared with 3% in the general population.[391] There is some evidence that the rate of individual cancers varies from kindred to kindred.[392-394]
Endometrial cancer
The most common extracolonic malignancy in Lynch syndrome is endometrial adenocarcinoma, which affects at least one female member in about 50% of Lynch syndrome families. In addition, 50% of women with an MMR gene pathogenic variant will present with endometrial cancer as her first malignancy.[395]
The lifetime risk of endometrial cancer has been estimated to be from 44% in carriers of MLH1 pathogenic variants to 71% in carriers of MSH2 pathogenic variants, although some earlier studies may have overestimated risk due to ascertainment bias.[6,259,353,360,396] Lifetime risk of endometrial cancer in carriers of MSH6 pathogenic variants in 113 families was estimated to be 26% at age 70 years and 44% at age 80 years;[6] overall, female carriers of MSH6 pathogenic variants had an endometrial cancer risk that was 25 times higher than women in the general population (HR, 25.5; 95% CI, 16.8–38.7; P < .001).[6] In another study, the cumulative lifetime risk of uterine cancer was higher in MSH6 carriers (71%) than in carriers of MLH1 (27%) and MSH2 (40%) pathogenic variants (P = .02), with an older mean age at diagnosis of 54 years in carriers of MSH6 pathogenic variants (n = 29; range, 43–65 y) versus 48 years in carriers of MLH1 and 49 years in carriers of MSH2pathogenic variants.[368] In carriers of PMS2 pathogenic variants, the endometrial cancer risk at age 70 years has been reported to be 15%.[372] Prospective data collected in the Colon Cancer Family Registry program yielded 5-year endometrial cancer risks of about 3% and 10-year endometrial cancer risks of about 10% among women with MMR gene pathogenic variants.[397] A prospective study using pooled European registry data of 1,942 MMR carriers without prior cancer reported a cumulative incidence of endometrial cancer of 34% in MLH1 carriers, 51% in MSH2 carriers, 49% in MSH6 carriers, and 24% in PMS2carriers.[5] Women with loss of MSH2 protein expression caused by an EPCAM pathogenic variant are also at risk of endometrial cancer depending upon the location of the variant in EPCAM. One study found a 12% (95% CI, 0%–27%) cumulative risk of endometrial cancer in EPCAM deletion carriers.[376]
A study of 127 women with Lynch syndrome who had endometrial cancer as their index cancer were found to be at significantly increased risk of other cancers. The following elevated risks were reported: CRC, 48% (95% CI, 27.2%–58.3%); kidney, renal pelvis, and ureter cancer, 28% (95% CI, 11.9%–48.6%); urinary bladder cancer, 24.3% (95% CI, 8.56%–42.9%; and breast cancer, 2.51% (95% CI, 1.17%–4.14%).[398]
In a study of 113 families that carried MSH6 pathogenic variants from the Colon Cancer Family Registry, female MSH6 carriers had a 26-fold increased incidence of endometrial cancer (HR, 25.5; 95% CI, 16.8–38.7) compared with the general population. A sixfold increased incidence of other cancers associated with Lynch syndrome (HR, 6.0; 95% CI, 3.4–10.7) was observed compared with the general population, but not among male MSH6carriers.[6]
Lynch syndrome–associated endometrial cancer is not limited to the endometrioid subtype, and the spectrum of uterine tumors in Lynch syndrome may include clear cell carcinoma, uterine papillary serous carcinoma, and malignant mixed Müllerian tumors.[399] Also, endometrial cancer most commonly arises from the lower uterine segment. (Refer to the Endometrial cancer screening in Lynch syndrome section of this summary for information about screening methods.)
Cancer risk in Lynch syndrome beyond CRC and endometrial cancer
Multiple studies demonstrate an increased risk of additional malignancies associated with Lynch syndrome, including cancers of the stomach, pancreas, ovary, small intestine, and brain, transitional cell carcinoma of the bladder, ureters, and renal pelvis, and sebaceous adenomas of the skin.[391,392,400-403] In addition, some studies have suggested an association with breast, prostate, and adrenal cortex cancers.[397,401,404-406] The strength of the association for many of these malignancies is limited by the majority of studies having a small sample size (and consequently, wide CIs associated with relative risk [RR]), the retrospective nature of the analyses, and referral or ascertainment bias.
The largest prospective study to date is of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry.[397] The Colon Cancer Family Registry is an international cohort with both population-based and clinic-based recruitment from six centers in North America and Australia. Control subjects were noncarriers from families with a known MMR pathogenic variant. Three subcohorts were used to analyze the risk of CRC (365 carriers, 903 noncarriers), endometrial cancer (215 carriers, 523 noncarriers), and other cancers (446 carriers, 1,029 noncarriers). Participants who were followed for up to 10 years demonstrated an increased SIR for CRC (SIR, 20.48; 95% CI, 11.71–33.27; P < .01), endometrial cancer (SIR, 30.62; 95% CI, 11.24–66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88–54.95; P < .001), gastric cancer (SIR, 9.78; 95% CI, 1.18–35.30; P = .009), renal cancer (SIR, 11.22; 95% CI, 2.31–32.79; P < .001), bladder cancer (SIR, 9.51; 95% CI, 1.15–34.37; P = .009), pancreatic cancer (SIR, 10.68; 95% CI, 2.68–47.70; P = .001), and female breast cancer (SIR, 3.95; 95% CI, 1.59–8.13; P = .001).[397]
A well-described variant of Lynch syndrome whose phenotype includes multiple cutaneous neoplasms (including sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas) and CRC is Muir-Torre syndrome.[407,408] Pathogenic variants in the MLH1, MSH2, and MSH6 genes have been found in Muir-Torre families with an increased prevalence described among MSH2 carriers.[409-416] A study of 1,914 unrelated MLH1 and MSH2 probands found MSH2 to be more common in individuals with the Muir-Torre syndrome phenotype. Of 15 individuals with sebaceous skin tumors, 13 (87%) had MSH2pathogenic variants compared with two individuals who had MLH1 pathogenic variants (P = .05).[417] Evidence of defective DNA MMR activity using IHC or MSI testing was reported in 69 of 163 randomly collected sebaceous neoplasms (42%), suggesting that this is a common mechanism for the development of these lesions, and that testing for defective MMR in sebaceous neoplasms would be an ineffective means to screen for Lynch syndrome or Muir-Torre syndrome.[418] (Refer to the Sebaceous Carcinoma section in the PDQ summary on Genetics of Skin Cancer for more information about cutaneous neoplasms in Muir-Torre syndrome.)
Additional cancers potentially associated with Lynch syndrome
Additional tumors are being considered as part of the spectrum of Lynch syndrome, but this is controversial. Breast and prostate cancers have been raised as possible Lynch syndrome–associated tumors such that MMR genes are now included on multigene (panel) tests for these cancers.
Breast cancer
The issue of breast cancer risk in Lynch syndrome has been controversial. Retrospective studies have been inconsistent, but several have demonstrated microsatellite instability in a proportion of breast cancers from individuals with Lynch syndrome;[434-437] one of these studies evaluated breast cancer risk in individuals with Lynch syndrome and found that it is not elevated.[437] However, the largest prospective study to date of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry [397] who were followed for up to 10 years reported an elevated SIR of 3.95 for breast cancer (95% CI, 1.59–8.13; P = .001).[397] The same group subsequently analyzed data on 764 carriers of MMR gene pathogenic variants with a prior diagnosis of colorectal cancer. Results showed that the 10-year risk of breast cancer following colorectal cancer was 2% (95% CI, 1%–4%) and that the SIR was 1.76 (95% CI, 1.07–2.59).[438] A series from the United Kingdom composed of clinically referred Lynch syndrome kindreds, with efforts to correct for ascertainment, showed a twofold increased risk of breast cancer in 157 MLH1carriers but not in carriers of other MMR variants.[439] Results from a meta-analysis of breast cancer risk in Lynch syndrome among 15 studies with molecular tumor testing results revealed that 62 of 122 breast cancers (51%; 95% CI, 42%–60%) in MMR pathogenic variant carriers were MMR-deficient. In addition, breast cancer risk estimates among a total of 21 studies showed an increased risk of twofold to 18-fold in eight studies that compared MMR variant carriers with noncarriers, while 13 studies did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome.[440]
A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[336,337,441,442] although this has not been consistently observed.[443] Through a study of 325 Canadian families with Lynch syndrome, primarily encompassing MLH1 and MSH2 carriers, the lifetime cumulative risk for breast cancer among MSH2 carriers was reported to be 22%.[441] Similarly, breast cancer risks were elevated in a study of 423 women with Lynch syndrome, with substantially higher risks among those with MSH6 and PMS2 pathogenic variants, compared with MLH1 and MSH2pathogenic variants.[337] In fact, breast cancer risk to age 60 years was 37.7% for PMS2, 31.1% for MSH6, 16.1% for MSH2, and 15.5% for MLH1. These findings are consistent with another study of 528 patients with Lynch syndrome–associated pathogenic variants (including MLH1, MSH2, MSH6, PMS2, and EPCAM) in which PMS2 and MSH6 variants were much more frequent among patients with only breast cancer, compared with those with only colorectal cancer (P = 2.3 x 105).[336] Additional data to support an association of MSH6 with breast cancer were provided through a study of over 10,000 cancer patients across the United States who had genetic testing.[442] Findings indicated that MSH6 was associated with breast cancer with an odds ratio (OR) of 2.59 (95% CI, 1.35–5.44). Taken together, these studies highlight how the risk profile among patients with Lynch syndrome is continuing to evolve as more individuals are tested through multigene panel testing, with representation of larger numbers of individuals with PMS2 and MSH6 pathogenic variants compared with prior studies. In the absence of definitive risk estimates, individuals with Lynch syndrome are screened for breast cancer on the basis of family history.[444]
Prostate cancer
Prostate cancer was found to be associated with Lynch syndrome in a study of 198 families from two U.S. Lynch syndrome registries in which prostate cancer had not originally been part of the family selection criteria. Prostate cancer risk in relatives of carriers of MMR gene pathogenic variants was 6.3% at age 60 years and 30% at age 80 years, versus a population risk of 2.6% at age 60 years and 18% at age 80 years, with an overall HR of 1.99 (95% CI, 1.31–3.03).[404] A 2014 meta-analysis supports this association, finding an estimated RR of 3.67 (95% CI, 2.32–6.67) for prostate cancer in men with a known MMR pathogenic variant.[445] This risk is possibly increased in those with MSH2 pathogenic variants.[406,445] Notwithstanding prevalent controversy surrounding routine prostate-specific antigen (PSA) screening, the authors suggested that screening by means of PSA and digital rectal exam beginning at age 40 years in male MMR gene carriers would be “reasonable to consider.”[404] A study of 692 men with metastatic prostate cancer unselected for family history of cancer or age at diagnosis identified germline MMR pathogenic variants in four men (0.5%).[446] Currently, molecular and epidemiologic evidence supports prostate cancer as one of the Lynch syndrome cancers. As with breast cancer,[445] additional studies are needed to define absolute risks and age distribution before surveillance guidelines for prostate cancer can be developed for carriers of MMR pathogenic variants. (Refer to the MMR Genes section in the PDQ summary on Genetics of Prostate Cancer for more information about prostate cancer and Lynch syndrome.)
Adrenocortical cancer
In a series of 114 ACC cases, of which 94 patients had a detailed family history assessment and Li-Fraumeni syndrome was excluded, three patients had family histories that were suggestive of Lynch syndrome. The prevalence of MMR gene pathogenic variants in 94 families was 3.2%, similar to the proportion of Lynch syndrome among unselected colorectal and endometrial cancer patients. In a retrospective review of 135 MMR gene pathogenic variant–positive Lynch syndrome families from the same program, two probands were found to have had a history of ACC. Of the four ACCs in which MSI testing could be performed, all were MSS. These data suggest that if Lynch syndrome is otherwise suspected in an ACC index case, an initial evaluation of the ACC using MSI or IHC testing may be misleading.[405]
Other cancers
Several additional cancers have been found to be associated with Lynch syndrome in some studies, but further investigation is warranted. Table 13 compares the risk of these cancers in the general population with that of individuals with Lynch syndrome.
Management of Lynch syndrome
Screening and surveillance in Lynch syndrome
Colon cancer screening and surveillance in Lynch syndrome
Several aspects of the biologic behavior of CRC and its precursor lesion, the adenomatous polyp, in individuals with Lynch syndrome support a different approach to CRC screening in this population as compared with those recommendations for average-risk people in the general population. At present, the recommendations for cancer screening and surveillance in Lynch syndrome take into account the differences in cancer risks as compared with those in the general population due to the causative germline deficiency in the MMR system. The following biological differences form the basis of the currently implemented screening strategies in Lynch syndrome:
- CRC and adenomas present at a younger age.CRCs in Lynch syndrome occur earlier in life than do sporadic cancers; however the age of onset varies based on which of the MMR genes is altered. (Refer to the Prevalence, clinical manifestations, and cancer risks associated with Lynch syndrome section of this summary for more information about gene-specific age of onset of CRC.)Carriers of Lynch syndrome pathogenic variants have an increased risk of developing colon adenomas and the onset of adenomas appears to occur at a younger age than in pathogenic variant–negative individuals from the same families.[447] The risk of a carrier of MMR pathogenic variants developing adenomas has been reported to be 3.6 times higher than the risk in noncarriers.[447] By age 60 years, 70% of the carriers developed adenomas, compared with 20% of noncarriers. Most of the adenomas in carriers had absence of MMR protein expression and were more likely to have dysplastic features, compared with adenomas from control subjects.[447]In one study, the mean age at diagnosis of adenoma in carriers was 43.3 years (range, 23–63.2 y), and the mean age at diagnosis of carcinoma was 45.8 years (range, 25.2–57.6 y).[447]
- There is a right-sided predominance of colon cancer.A larger proportion of Lynch syndrome CRCs (60%–70%) occur in the right colon, suggesting that sigmoidoscopy alone is not an appropriate screening strategy and that a colonoscopy provides a more complete structural examination of the colon. Evidence-based reviews of surveillance colonoscopy in Lynch syndrome have been reported.[144,448,449] The incidence of CRC throughout life is substantially higher in patients with Lynch syndrome, suggesting that the most-sensitive test available should be used. (Refer to Table 14 for available colon surveillance recommendations.)
- The adenoma-carcinoma sequence is accelerated.The progression from normal mucosa to adenoma to cancer is accelerated,[450,451] suggesting that screening should be performed at shorter intervals (every 1–2 years) and with colonoscopy.[451-454] It has been demonstrated that carriers of MMR gene pathogenic variants develop detectable adenomas at an earlier age than do noncarriers.[447,447] It is not known whether this reflects a greater prevalence of adenomas or the presence of larger adenomas with better detection in Lynch syndrome.
Evidence for the use of colonoscopy for CRC screening and surveillance in Lynch syndrome
The risk of CRC in Lynch syndrome has been studied and updated in a Finnish screening trial, which spans from the early 1980s to present.[451,455] Over the course of this trial, the design of the longitudinal study has evolved. In the earliest period, information about each individual's variant status was unknown and study participants were eligible based on fulfillment of clinical criteria; the study consisted of some people with a previous cancer or adenoma diagnosis and others without such history who were undergoing asymptomatic screening while the comparison group was composed of individuals from those same families who refused screening. Many of these people (68%) had screening with x-ray contrast/barium enema. Colonoscopy was the approach used for carriers of MMR pathogenic variants when this information was obtainable and the interval between exams was shortened from 5 years to 3 years to 2 years, based on results from the study over time.
A 15-year controlled screening trial conducted in this series demonstrated a reduction in the incidence of CRC, CRC-specific mortality, and overall mortality with colonoscopy in individuals from Lynch syndrome families.[451] Colonic screening was provided at 3-year intervals in 133 individuals from Lynch syndrome families and 119 controls from these families had no screening. Among those screened, 8 individuals (6%) developed CRC compared with 19 control subjects (16%), for a risk reduction of 62% with screening. Furthermore, all CRCs in the screened group were local, causing no deaths, while there were 9 deaths caused by CRC in the control group. There was also a benefit in overall mortality in the screened group with 10 deaths in the screened group and 26 deaths in the control group (P = .003).
The series subsequently limited its attention to subjects without prior diagnosis of adenoma or cancer. The eligible 420 carriers of pathogenic variants had a mean age of 36 years and underwent an average of 2.1 colonoscopies, with a median follow-up of 6.7 years. Adenomas were detected in 28% of subjects. Cumulative risk of one or more adenomas by age 60 years was 68.5% in men and 48.3% in women. Notably, risk of detecting cancer in those free of cancer at baseline exam, and thus regarded as interval cancers, by age 60 years was 34.6% in men and 22.1% in women. The combined cumulative risk of adenoma or cancer by age 60 years was 81.8% in men and 62.9% in women. For both adenomas and carcinomas, about one-half were located proximal to the splenic flexure. While the rates for CRC despite colonoscopy surveillance appear high, the recommended short intervals were not regularly adhered to in this nonrandomized series. These authors recommended surveillance at 2-year intervals. This is in line with most consensus guidelines (refer to Table 14), in which the appropriate colonoscopy screening interval remains every 1 to 2 years. Analysis of colonoscopic surveillance data in 242 carriers of pathogenic variants 10 years after testing shows 95% compliance in surveillance procedures for CRC and endometrial cancer. Although not all CRCs were prevented, mortality was comparable with variant-negative relatives. However, this may be attributable to the modest sample size of the study.[455]
Given that colonoscopy is the accepted measure for colon cancer surveillance, preliminary data suggest that the use of chromoendoscopy, such as with indigo carmine, may increase the detection of diminutive, histologically advanced adenomas.[456,457]
When an adenoma is detected, the question of whether to test the adenoma for MSI/IHC is raised. One study of patients with prior CRC and known MMR pathogenic variants found eight of 12 adenomas to have both MSI and IHC protein loss.[458] However, the study authors emphasized that normal MSI/IHC testing in an adenoma does not exclude Lynch syndrome. Abnormal MSI/IHC are uncommon in the smallest adenomas, and more prevalent in adenomas larger than 8 mm, which also suggests that the MMR defect is acquired in the growing adenoma.[235]
Special considerations: The impact of gene-specific variability in cancer risk on CRC screening recommendations in Lynch syndrome
Because of the variability of gene-specific CRC risks, experts in the field have proposed gene-specific screening and surveillance recommendations. For example, a European consortium [373] made a clinical recommendation for delaying the onset of colorectal and endometrial cancer screening to age 30 years, in line with their recommendation for later initiation of screening for carriers of MSH6 pathogenic variants. Additionally, a 2015 review by an ad hoc American virtual workgroup involved in the care of Lynch syndrome patients and families concluded that despite multiple studies indicating reduced penetrance in monoallelic PMS2 carriers, they could not recommend any changes to Lynch syndrome cancer surveillance guidelines for this group.[369]
While initial data may support different strategies for the initiation and surveillance of CRC and other extracolonic cancers by specific MMR gene alteration,[397] concerns related to (a) the adherence of recommendations overall by the medical community and by affected individuals [459] and (b) limitations related to specific screening modalities [460] have prevented the implementation of gene-specific guidelines until additional data are available.[95]
Extracolonic cancer screening in Lynch syndrome
Gynecologic cancer screening in Lynch syndrome
Endometrial cancer screening in Lynch syndrome
Note: A separate PDQ summary on Endometrial Cancer Screening in the general population is also available.
Cancer of the endometrium is the most common extracolonic cancer observed in Lynch syndrome families, affecting at least one female in about 50% of Lynch syndrome families. (Refer to the Endometrial cancer section of this summary for more information about gene-specific risks of endometrial cancer in carriers of MMR pathogenic variants.)
In the general population, the diagnosis of endometrial cancer is generally made when women present with symptoms including abnormal or postmenopausal bleeding. Endometrial sampling is performed to provide a histologic specimen for diagnosis. Eighty percent of women with endometrial cancer present with stage I disease and there are no data to suggest that the clinical presentation in women with Lynch syndrome differs from that in the general population.
Given their substantial increased risk of endometrial cancer, endometrial screening for women with Lynch syndrome has been suggested. Proposed modalities for screening include transvaginal ultrasound (TVUS) and/or endometrial biopsy. TVUS continues to be widely recommended without data to support its use; current NCCN guidelines suggest that there is no clear evidence to support endometrial cancer screening for Lynch syndrome.[95] Two studies have examined the use of TVUS in endometrial screening for women with Lynch syndrome.[465,466] In one study of 292 women from Lynch syndrome families or "Lynch syndrome-like/HNPCC-like" families, no cases of endometrial cancer were detected by TVUS. In addition, two interval cancers developed in symptomatic women.[465] In a second study, 41 women with Lynch syndrome were enrolled in a TVUS screening program. Of 179 TVUS procedures performed, there were 17 abnormal scans. Three of the 17 women had complex atypical hyperplasia on endometrial sampling, while 14 had normal endometrial sampling. However, TVUS failed to identify one patient who presented 8 months after a normal TVUS with abnormal vaginal bleeding, and was found to have stage IB endometrial cancer.[466] Both of these studies concluded that TVUS is neither sensitive nor specific.
A study of 175 women with Lynch syndrome, which included both endometrial sampling and TVUS, showed that endometrial sampling improved sensitivity compared with TVUS. Endometrial sampling found 11 of the 14 cases of endometrial cancer. Two of the three other cases were interval cancers that developed in symptomatic women and one case was an occult endometrial cancer found at the time of hysterectomy. Endometrial sampling also identified 14 additional cases of endometrial hyperplasia. Among the group of 14 women with endometrial cancer, ten also had TVUS screening with endometrial sampling. Four of the ten had abnormal TVUS, but six had normal TVUS.[467] While this cohort study demonstrated that endometrial sampling may have benefits over TVUS for endometrial screening, there are no data that predict that screening with any other modality has benefits for endometrial cancer survival in women with Lynch syndrome.
Some studies suggest that women with a clinical or genetic diagnosis of Lynch syndrome do not universally adopt intensive gynecologic screening.[468,469] (Refer to the Gynecologic cancer screening in Lynch syndrome section in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for more information.)
Ovarian cancer screening in Lynch syndrome
Estimates of the cumulative lifetime risk of ovarian cancer in Lynch syndrome patients range from 3.4% to 22%.[4,353,422-424] However, no studies on the effectiveness of ovarian screening are currently available for women in Lynch syndrome families. TVUS used for endometrial cancer screening has been extended to include ovarian cancer screening in clinical practice for those women who do not undergo risk-reducing surgery for gynecological cancer prevention. However, NCCN asserts that data do not support routine ovarian cancer screening for Lynch syndrome due to a lack of sensitivity and specificity of available screening modalities.[95]
Level of evidence: None assigned
Risk-reducing surgeries for the prevention of gynecologic cancers in Lynch syndrome
An effective strategy for the prevention of endometrial and ovarian cancers in Lynch syndrome families is risk-reducing surgery. A retrospective study of 315 women with pathogenic MMR gene variants compared the rate of endometrial and ovarian cancer among the women who did and did not have hysterectomy and oophorectomy. In women followed for endometrial cancer, the mean follow-up periods were 13.3 years in the surgical group and 7.4 years in the nonsurgical group; in women followed for ovarian cancer, the mean follow-up periods were 11.2 years in the surgical group and 10.6 years in the nonsurgical groups. For those women in the surgical group, no cancers were diagnosed, compared with a 33% rate of endometrial cancer and a 5.5% rate of ovarian cancer in the nonsurgical group.[470] Cost-effectiveness–analysis modeling of risk-reducing surgeries (prophylactic hysterectomy and bilateral salpingo-oophorectomy) versus nonsurgical screening in a theoretical population of carriers aged 30 years with MMR gene variants associated with Lynch syndrome revealed that prophylactic surgery was cost-effective with lower cost and yielded higher QALY.[429] A subsequent modeling study evaluated multiple screening and surgical strategies and found that annual screening initiated at age 30 years followed by risk-reducing surgery at age 40 years was the most effective strategy.[471]
Additional extracolonic cancer screening in Lynch syndrome
The decision to screen for other Lynch syndrome–associated cancers is done on an individual basis and relies on the cancers reported among FDRs and second-degree relatives with Lynch syndrome.
Gastric cancer
The lifetime risk of gastric cancer is approximately 8% for male Lynch syndrome carriers and 5% for female Lynch syndrome carriers.[425] Recent epidemiologic data report a decreasing trend in the diagnosis of gastric cancer than was previously reported, which was as high as 13%. The histologic characterization of most Lynch syndrome–associated gastric cancer is of the intestinal type and may thereby be detected using screening esophagogastroduodenoscopy (EGD).[425,472] Although there are no clear data to support surveillance for gastric, duodenal, and more distal small bowel cancers, EGD with visualization of the duodenum at the time of colonoscopy can be used in individuals with Lynch syndrome with a baseline examination performed at age 40 years. Evaluation and treatment of Helicobacter pylori infection is recommended when found. Despite limited data on appropriate surveillance intervals, there is general consensus that surveillance be performed every 3 to 5 years, particularly if there is a family history of gastric, duodenal, or more distal small bowel cancer or for those of Asian descent.[95]
Small bowel cancer
There are variable reports on the lifetime risk of small bowel cancer associated with Lynch syndrome, ranging from less than 1% to 12%.[4,359,421-423,426] Most small bowel malignancies are confined to the duodenum and the ileum, which are within endoscopic reach using EGD and colonoscopy (with dedicated ileal intubation), respectively. Other modalities to assess for small bowel lesions include CT enterography and capsule endoscopy but cost-effectiveness analyses do not support use of these evaluations for routine screening in Lynch syndrome.[424]
Urinary tract cancer
Urinary tract malignancies include those of the transitional cell type of the renal pelvis and ureters, and the bladder. The associated lifetime risk of these malignancies is variable, ranging from less than 1% to as high as 25%, with higher estimates related to pooling the cancers found in different locations within the urinary tract and including the bladder.[4,359,422,423,426,427] Studies that have evaluated urinary cytology as a potential screening modality revealed that it was associated with low sensitivity and a high false-positive rate and ultimately leads to additional evaluation that is often invasive (i.e., cystoscopy). There are currently no effective modalities used for routine screening in asymptomatic individuals with Lynch syndrome.
Pancreatic cancer
An elevated risk of pancreatic cancer among Lynch syndrome carriers has been supported by two cohort studies that adjust for ascertainment bias. One study reported a cumulative risk of pancreatic cancer of 3.7% by age 70 years and an 8.6-fold increase compared with the general population. [433] Another prospective study using data from the Colon Cancer Family Registry reported an SIR of 10.7 with cumulative risk of 0.95%.[397] Results of these studies have supported an expert consensus that recommended screening for pancreatic cancer in individuals with Lynch syndrome and an FDR with pancreatic cancer, similar to other high-risk populations with comparable risk.[473]
Of note, screening for cancers of the urinary tract, bladder, hepatobiliary system, and pancreas is not recommended beyond that for the general population; however, NCCN suggests the consideration of urothelial cancer screening for individuals with a family history of urothelial cancer or individuals with MSH2 pathogenic variants (especially males).[95]
Chemoprevention in Lynch syndrome
The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP2) was a double-blind, placebo-controlled, randomized trial to determine the role of aspirin in preventing CRC in patients with Lynch syndrome who were in surveillance programs at a number of international centers.[474] The study randomly assigned 861 participants to receive aspirin (600 mg/day), aspirin placebo, resistant starch (30 g/day), or starch placebo for up to 4 years. At a mean follow-up of 55.7 months (range, 1–128 months), 53 primary CRCs developed in 48 participants (18 of 427 in the aspirin group and 30 of 434 in the aspirin placebo group). Seventy-six patients who refused randomization to the aspirin groups (because of an aspirin sensitivity or a history of peptic ulcer disease) were randomly assigned to receive resistant starch or resistant starch placebo. The intent-to-treat analysis yielded an HR for CRC of 0.63 (95% CI, 0.35–1.13; P = .12). However, five of the patients who developed CRC developed two primary colon cancers. A Poisson regression was performed to account for the effect of the multiple primary CRCs and yielded a protective effect for aspirin (incidence rate ratio [IRR], 0.56; 95% CI, 0.32–0.99; P = .05). For participants who completed at least 2 years of treatment, the per-protocol analysis yielded an HR of 0.41 (95% CI, 0.19–0.86; P = .02) and an IRR of 0.37 (0.18–0.78; P = .008). An analysis of all Lynch syndrome cancers (endometrial, ovarian, pancreatic, small bowel, gallbladder, ureter, stomach, kidney, and brain) revealed a protective effect of aspirin versus placebo (HR, 0.65; 95% CI, 0.42–1.00; P = .05). There were no significant differences in adverse events between the aspirin and placebo groups, and no serious adverse effects were noted with any treatment. The authors concluded that 600 mg of aspirin per day for a mean of 25 months substantially reduced cancer incidence in Lynch syndrome patients. CAPP2 failed to show any effect from daily resistant starch intake. A limitation of the trial is that the frequency of surveillance studies at the various centers was not reported as being standardized. Earlier CAPP2 trial results for 746 Lynch syndrome patients enrolled in the study were published in 2008 [475] and failed to show a significant preventive effect on incident colonic adenomas or carcinomas (relative risk, 1.0; 95% CI, 0.7–1.4) with a shorter mean follow-up of 29 months (range, 7–74 months). A 2015 survey of 1,858 participants in the Colon Cancer Family Registry suggested that aspirin and ibuprofen might be chemopreventive for carriers of MMR gene pathogenic variants.[476] The CAPP3 trial, which is evaluating the effect of lower doses of aspirin (blinded 100 mg, 300 mg, and 600 mg enteric-coated aspirin), began in 2013 and is expected to enroll approximately 3,000 carriers of pathogenic variants by about 2021.[477]
Despite level 1 evidence, experts believe that the evidence regarding aspirin use for the chemoprevention of Lynch syndrome is not sufficiently robust or mature to recommend its standard use.[419]
Management of Lynch syndrome-associated CRC
Surgical management of CRC in Lynch syndrome
One of the hallmark features of Lynch syndrome is the presence of synchronous and metachronous CRCs. The incidence of metachronous CRCs has been reported to be 16% at 10 years, 41% at 20 years, and 63% at 30 years after segmental colectomy.[389] Because of the increased incidence of synchronous and metachronous neoplasms, the recommended surgical treatment for a patient with Lynch syndrome with neoplastic colonic lesions is generally an extended colectomy (total or subtotal). Nevertheless, treatment has to be individualized and has often included segmental colectomy. Mathematical models suggest that there are minimal benefits of extended procedures in individuals older than 67 years, compared with the benefits seen in younger individuals with early-onset cancer. In one Markov decision analysis model, the survival advantage for a young individual with early-onset CRC undergoing an extended procedure could be up to 4 years longer than that seen in the same individual undergoing a segmental resection.[478] The recommendation for an extended procedure must be balanced with the comorbidities of the patient, the clinical stage of the disease, the wishes of the patient, and surgical expertise. No prospective or retrospective study has shown a survival advantage for patients with Lynch syndrome who underwent an extended resection versus a segmental procedure.
Two studies have shown that patients who undergo extended procedures have fewer metachronous CRCs and additional surgical procedures related to CRC than do patients who undergo segmental resections.[389,479] Balancing functional results of an extended procedure versus a segmental procedure is of paramount importance. Although the majority of patients adapt well after an abdominal colectomy, some patients will require antidiarrheal medication. A decision model compared QALYs for a patient aged 30 years undergoing an abdominal colectomy versus a segmental colectomy.[480] In this model, there was not much difference between the extended and segmental procedure, with QALYs being 0.3 years more in patients undergoing a segmental procedure than in those undergoing an extended procedure.[480]
When considering surgical options, it is important to recognize that a subtotal or total colectomy will not eliminate the rectal cancer risk. The lifetime risk of developing cancer in the rectal remnant after an abdominal colectomy has been reported to be 12% at 12 years post-colectomy.[481] In addition to the general complications of surgery are the potential risks of urinary and sexual dysfunction and diarrhea after an extended colectomy; these risks increase as the anastomosis becomes more distal. Therefore, the choice of surgery must be made on an individual basis by the surgeon and the patient.
In patients with Lynch syndrome and rectal cancer, similar surgical options (extended vs. segmental resection) and considerations must be given. Extended procedures include restorative proctocolectomy and IPAA if the sphincter can be saved, or proctocolectomy with loop ileostomy if the sphincter cannot be saved. The risk of metachronous colon cancer after segmental resection for an index rectal cancer has been reported to be between 15% and 27%.[438,482] Two retrospectives studies reported a 15% and 18% incidence of metachronous colon cancer after segmental rectal cancer–resection in patients with Lynch syndrome.[483,484] In one of the studies, the combined risk of metachronous high-risk adenomas and cancers was 51% at a median follow-up of 101.7 months after proctectomy.[484]
There are no data about fertility after surgery in Lynch syndrome patients. In female FAP patients, no difference in fecundity after abdominal colectomy and IRA has been reported, whereas there is a 54% decrease in fecundity in patients who undergo restorative proctocolectomy with IPAA compared with the general population.[485] Another study in which a questionnaire was sent to FAP patients reported a similar prevalence of fertility problems among patients who had undergone IRA, IPAA, and proctocolectomy with end ileostomy. In that study, it was reported that earlier age at the time of surgery was associated with more fertility problems.[486]
Prognostic and therapeutic implications of MSI
As discussed in previous sections, MSI is not only a molecular feature of Lynch syndrome, but is also present in 10% to 15% of sporadic cases of CRC (largely due to MLH1hypermethylation or biallelic somatic pathogenic variants in an MMR gene). Although MSI testing was initially utilized to screen patients who might harbor pathogenic MMR gene variants, it has been increasingly recognized that MSI has important prognostic and therapeutic implications. The utility of MSI testing beyond identifying Lynch syndrome has made the case for universal MSI screening more compelling, and has contributed to its widespread adoption. Several studies have suggested that stage-specific survival is better for MSI-H CRC compared with MSS cancers. Additionally, the chemotherapeutic agent 5-fluorouracil (5-FU) appears ineffective in the adjuvant treatment of resected MSI-H CRC, in contrast to MSS CRC in which this agent is widely utilized for this purpose. Finally, immunomodulation with agents such as checkpoint inhibitors appears effective in the treatment of advanced MSI-H CRC based on early phase 1 and phase 2 studies, while these agents, at least when utilized as monotherapy, show little activity in MSS CRC.
Prognosis of MSI
Although MSI-H tumors account for 15% of all sporadic CRC, they appear to be more frequent in stage II compared with stage III CRC,[489] and are even less common in metastatic disease, being present in only 3% to 4% of metastatic cases.[490] This stage distinction alludes to the possibility of a better prognosis associated with underlying MSI-H status.
Several studies subsequently confirmed the improved survival of stage II MSI-H CRC compared with MSS cases. A meta-analysis of 32 studies of 7,642 cases, including 1,277 with MSI-H, showed a combined HR estimate for overall survival (OS) associated with MSI of 0.65 (95% CI, 0.59–0.71; heterogeneity P = .16; I2 [a measure of the percentage of variation across studies that is due to heterogeneity rather than chance] = 20%).[491] However, while data were limited, tumors with MSI derived no benefit from adjuvant 5-FU (HR, 1.24; 95% CI, 0.72–2.14). Subsequent data from several large randomized clinical trials confirmed the favorable prognosis associated with MSI-H. These included the QUick And Simple And Reliable (QUASAR) trial, which explored the benefit of adjuvant 5-FU–based chemotherapy compared with surgery alone in 1,900 patients with resected stage II CRC. In this study, MSI-H tumors were associated with a recurrence risk of half that of MSS tumors (risk ratio [RR], 0.53; 95% CI, 0.40–0.70).[492] Similar results were seen in the Pan European Trial Adjuvant Colon Cancer (PETACC)-3 trial, a randomized trial of 5-FU with or without irinotecan in resected stage II or stage III CRC.[493] MSI-H status was associated with an OS odds ratio (OR) of 0.39 (95% CI, 0.24–0.65) and this advantage was seen in both stage II and stage III disease.
Consistent with other prior data, clinicopathologic analysis of 85 Lynch syndrome–associated CRCs and 67 sporadic MMR-deficient (dMMR) CRCs demonstrated a significantly superior survival among patients with Lynch syndrome, as well as younger ages at diagnosis and higher numbers of tumor-infiltrating lymphocytes (TILs).[494] Exome sequencing and neoantigen data from a subset of 16 CRC tumors (eight Lynch syndrome CRCs and eight sporadic dMMR CRCs) from this cohort suggest that somatic mutational burden and neoantigen load is significantly higher among Lynch syndrome–associated CRCs than sporadic dMMR CRCs; this was speculated to be the source of the improved survival outcomes and increased TILs.
Given the predilection for MSI-H tumors to involve the right side of the colon, there is a paucity of data on the outcome and prognosis of MSI-H tumors involving the rectum. One study suggested only 2% of rectal cancers are MSI-H.[492] A study of 62 patients with MSI-H rectal cancers from a single institution were followed for a median of 6.8 years. The 5-year rectal cancer–specific survival was 100% for stage I and stage II, 85.1% for stage III, and 60.0% for stage IV disease, suggesting the favorable prognosis associated with MSI-H may also apply to cancers involving the rectum.[482] The authors additionally reported a favorable 26% pathologic complete response (pCR) rate with 5-FU combined with radiation therapy, suggesting that 5-FU given with radiation for the locoregional treatment of rectal cancer may still be effective in the setting of MSI-H tumors. The substantial rate of pCRs demonstrated in this study also reinforces the need for adequate biopsies to assess MSI status prior to commencing treatment.
The use of adjuvant chemotherapy after surgery for CRC in Lynch syndrome
The finding of MSI in a CRC has been shown in several studies to predict the lack of benefit of adjuvant chemotherapy with 5-FU in resected stage II or stage III colon cancer.[495] This has been a controversial area historically. It was known that loss of DNA MMR activity in cultured colon cancer cells conferred resistance to DNA-damaging agents (the common mechanism of cytotoxic chemotherapy) through loss of the signal to arrest the cell cycle in response to DNA damage that cannot be repaired.[496] This led to the prediction that DNA dMMR tumors may not be fully sensitive to alkylating agents, 5-FU, and platinum-containing drugs.[497-499] Unexpectedly, in 2000, a paper was published suggesting that patients with Dukes C (stage III) CRC with MSI had a substantial survival benefit when given 5-FU–based adjuvant chemotherapy.[500] However, the patients in this analysis had not been randomized to therapy; they were selected for adjuvant chemotherapy based upon clinical status, and inadvertently, the median age in the treatment group was 13 years younger than the controls.
In 2003, however, the outcomes in a randomized controlled prospective trial of adjuvant chemotherapy in 570 colon cancer patients demonstrated no benefit from adjuvant 5-FU in the group with MSI. Moreover, there were nonsignificant trends towards increased mortality when colon cancers with MSI were treated: twofold for stage III cancers and threefold for stage II cancers.[501] Subsequently, ten studies confirmed this, as all failed to show benefit when CRC patients were given 5-FU–based chemotherapy.[495] In contrast, a meta-analysis of randomized trials of 5-FU versus observation suggested a potential benefit of 5-FU in patients with MSI stage III disease. An exploratory subset analysis suggested benefit only in those patients with Lynch syndrome–related MSI. An analysis of stage II patients was not undertaken in this study.[502]
Preclinical data suggests the addition of oxaliplatin to 5-FU can overcome the resistance to 5-FU monotherapy seen in MSI-H tumors.[503] A retrospective analysis of 433 MSI-H stage II and stage III CRC cases (both sporadic and secondary to Lynch syndrome) suggested a benefit in disease-free survival (DFS) with FOLFOX (5-FU and oxaliplatin) compared with surgery alone.[504] There was a trend towards improved DFS utilizing FOLFOX in the subset of patients with MSI due to Lynch syndrome, however, the result was not statistically significant. Additional studies have demonstrated similar survival outcomes irrespective of MSI status with adjuvant chemotherapy including FOLFOX.[505,506]
Immunotherapy
Tumors that develop via the MSI pathway have more somatic variants than tumors that develop via other pathways. This could imply that dMMR tumors may have more potential antigens (termed neoantigens) and may be more responsive to immune system manipulation than proficient MMR (pMMR) tumors. Microscopically, MSI-H tumors often exhibit abundant tumor-infiltrating lymphocytes, sometimes resulting in a Crohn-like reaction. This histologic feature has long suggested the possibility of increased tumor immune surveillance in MSI-H cancers, and is one of the main hypotheses for the better stage-specific survival seen in MSI-H compared with MSS cancers.
To test the hypothesis of efficacy of immunomodulation in MSI-H tumors, a phase 2 trial of programmed cell death-1 (PD-1) inhibition was carried out in a small cohort of patients with MSI-H or MSS cancers. Patients with metastatic disease that had failed various chemotherapy regimens were treated with pembrolizumab, an anti–PD-1 immune checkpoint inhibitor.[507] In this small phase 2 study, 32 patients with CRC (11 were dMMR, 21 were pMMR, and 9 others had noncolorectal dMMR tumors) were treated with intravenous pembrolizumab every 14 days. The immune-related response among evaluable patients was 40% (4 of 10) for dMMR CRC tumors, 0% (0 of 18) for pMMR CRC tumors, and 71% (5 of 7) for non-CRC dMMR tumors. The immune-related 20-week progression-free survival (PFS) was 78% (7 of 9) in patients with dMMR CRC tumors, 11% (2 of 18) in patients with pMMR CRC tumors, and 67% (4 of 6) in patients with non-CRC dMMR tumors. dMMR tumors had a mean of 24-fold more somatic variants than pMMR tumors. Additionally, in this study somatic variant load was associated with prolonged PFS. The authors concluded that MMR status predicted clinical benefit to immune checkpoint blockade with pembrolizumab.
A single-arm phase 2 study (CheckMate 142) of another PD-1 inhibitor, nivolumab, was performed in 74 patients with MSI-H/dMMR CRC that had progressed on prior cytotoxic chemotherapy (including 5-FU, irinotecan, and oxaliplatin).[508] Overall, 31% of patients (23 of 74) experienced an objective response to therapy, and 69% (51 of 74) had disease control for at least 12 weeks. Among patients who responded to nivolumab, the median duration of response was not reached at the time of study analysis (median follow up of 12 months). There was no significant difference in the response rates among individuals with Lynch syndrome–associated metastatic MSI-H/dMMR CRC versus non-Lynch metastatic MSI-H/dMMR CRC in this study. Twenty percent of study participants experienced grade 3 or greater toxicities, most commonly elevations in amylase and/or lipase, and there were no deaths that were attributed to nivolumab.
Based on these data, pembrolizumab 200 mg given intravenously every 3 weeks was approved by the FDA in May 2017 for the treatment of any MSI-H/dMMR metastatic cancer that is refractory to standard therapy and nivolumab 240 mg given intravenously every 2 weeks was granted accelerated approval by the FDA in August 2017 for the treatment of MSI-H/dMMR CRC that is refractory to cytotoxic chemotherapy.
In another arm of CheckMate 142, 119 individuals with metastatic dMMR CRC were treated with nivolumab plus ipilimumab.[509] The objective response rate was 55% with a 12-week disease control rate of 80%, a 12-month PFS of 71%, and a medial duration of response that was not reached. Grade 3 and grade 4 toxicities occurred in 32% of participants (most commonly increased liver function tests) and 13% of all participants discontinued therapy due to toxicity. This was a nonrandomized study, and thus questions remain as to whether the combination of immune checkpoint blockade is superior to PD-1 inhibition alone, especially given the apparent increase in toxicity with combination therapy. On the basis of these data, in July 2018 the FDA granted accelerated approval to nivolumab plus ipilimumab therapy for the treatment of dMMR/MSI-H metastatic CRC that has progressed through prior chemotherapy with a fluoropyrimidine, oxaliplatin, and irinotecan.
Vaccines in the treatment or prevention of MSI-related CRC
An alternative approach to immunotherapy in MSI-H CRC involves the use of tumor-directed vaccines. The most promising approaches thus far involve the use of tumor-related neoantigens as epitopes to increase tumor-specific T-cell immunity. Studies are currently under way in the adjuvant treatment of resected stage III CRC (NCT01461148), in patients with metastatic disease (NCT01885702), and in the prevention of CRC in patients with Lynch syndrome (NCT01885702).
Lynch syndrome–related syndromes
Lynch-like or HNPCC-like syndrome
Lynch-like syndrome may account for up to 70% of cases in which Lynch syndrome is suspected but germline testing fails to identify a pathogenic MMR gene variant.[296] Similar to the tumor phenotype seen in Lynch syndrome, CRCs manifest MSI and IHC loss of a DNA MMR protein. However, the MMR-deficient CRCs are due to biallelic somatic inactivation of DNA MMR genes,[510-512] in which a somatic variant in one allele of the MMR gene along with loss of heterozygosity of the other allele is most probable versus the presence of two somatic sequence variants. (Refer to Table 11 for more information about the tumor phenotype of Lynch-like syndrome.)
Possible explanations for the cause of Lynch-like syndrome include the following: (1) the possibility that some germline DNA variants are not detected by current testing; (2) affected individuals may have germline pathogenic variants in genes other than DNA MMR genes currently known to be associated with Lynch syndrome; or (3) there are other mechanisms that inactivate DNA MMR beyond those related to alterations in the germline.
There is growing evidence that the CRC risk among probands and families with Lynch-like syndrome are lower, with an SIR of 2.12, than in Lynch syndrome, with an SIR of 6.04.[296] Preliminary estimates reveal a lower risk of extracolonic cancers with a SIR of 1.69 in Lynch-like syndrome versus 2.81 in Lynch syndrome. In the absence of large-scale studies with longitudinal follow-up, in addition to data pertaining to the rates of neoplastic progression in Lynch-like syndrome, intensive cancer screening recommendations are currently similar to those in Lynch syndrome guidelines.
Familial colorectal cancer type X
The term familial colorectal cancer type X or FCCX was coined to refer to families who meet Amsterdam criteria but lack MSI/IHC abnormalities.[251] Approximately 50% of families that fulfill Amsterdam criteria, lack pathogenic MMR gene variants and thereby are characterized as FCCX families. Research is ongoing to determine a genetic etiology for FCCX, but for the most part it remains unknown and is thought to be a heterogeneous condition. However, differentiating between Lynch syndrome and FCCX has important implications regarding cancer risk assessment and screening recommendations for affected individuals and at-risk relatives. While the risk of CRC is increased to twice that in the general population, it is less than that in Lynch syndrome (>sixfold increase) and there is no significant risk of extracolonic malignancy. Cancer screening recommendations are therefore modified and CRC surveillance is recommended every 5 years.[251]
Special considerations: Young-onset CRC
The epidemiology of CRC with regard to age at diagnosis is shifting with individuals increasingly being diagnosed before age 50 years.[513] (Refer to the PDQ summary on Colorectal Cancer Prevention for more information about CRC incidence trends in the general population.) One study that examined the prevalence of highly penetrant pathogenic variants in 450 individuals with young-onset CRC (mean age at diagnosis, 42.5 y) and a family history including at least one FDR with colon, endometrial, breast, ovarian, and/or pancreatic cancer identified 75 germline pathogenic or likely pathogenic variants in 72 patients (16%).[333] The spectrum of variants identified included Lynch syndrome and non-Lynch syndrome–associated genes, including several genes that have not traditionally been associated with CRC (e.g., BRCA1/BRCA2, ATM, CHEK2, PALB2, and CDKN2A). Given the high frequency and variety of hereditary cancer syndromes identified, the authors suggest that multigene (panel) testing in this population may be warranted.
In the absence of additional family or personal history suggestive of Lynch syndrome, isolated cases of CRC diagnosed before age 36 years are uncommonly associated with MMR gene pathogenic variants. One study found MMR pathogenic variants in only 6.5% of such individuals,[514] whereas another study of CRC patients younger than 50 years with no more than one FDR with CRC found abnormal MSI in 21% of tumors and overrepresentation of defects in the PMS2 and MSH6 genes.[515] Therefore, isolated cases of very early-onset CRC should be offered tumor screening with MSI/IHC rather than proceeding directly to germline pathogenic variant analysis.
Advances in Endoscopic Imaging in Hereditary CRC
Performance of endoscopic therapies for adenomas in FAP and Lynch syndrome, and decision-making regarding surgical referral and planning, require accurate estimates of the presence of adenomas. In both AFAP and Lynch syndrome the presence of very subtle adenomas poses special challenges—microadenomas in the case of AFAP and flat, though sometimes large, adenomas in Lynch syndrome.
Chromoendoscopy
The need for sensitive means to endoscopically detect subtle polyps has increased with the recognition of flat adenomas and sessile serrated polyps in otherwise average-risk subjects, very attenuated adenoma phenotypes in AFAP, and subtle flat adenomas in Lynch syndrome. Modern high-resolution endoscopes improve adenoma detection yield, but the use of various vital dyes, especially indigo carmine dye-spray, has further improved detection. Several studies have shown that the improved mucosal contrast achieved with the use of indigo carmine can improve the adenoma detection rate. Whether family history is significant or not, careful clinical evaluation consisting of dye-spray colonoscopy (indigo carmine or methylene blue),[456,516-521] with or without magnification, or possibly newer imaging techniques such as narrow-band imaging,[522] may reveal the characteristic right-sided clustering of more numerous microadenomas. Upper GI endoscopy may be informative if duodenal adenomas or fundic gland polyps with surface dysplasia are found. Such findings will increase the likelihood of variant detection if APC or MUTYH testing is pursued.
In various large series of average-risk populations, subtle flat lesions were detected in about 5% to 10% of cases, including adenomas with high-grade dysplasia and invasive adenocarcinoma.[523] Some of these studies involved tandem procedures—white-light exam followed by randomization to “intensive” (> 20-minute pull-back from cecum) inspection versus chromoendoscopy—with significantly more adenomas detected in the chromoendoscopy group.[524] However, in several randomized trials, no significant difference in yield was seen.[525,526]
In a randomized trial of subjects with Lynch syndrome,[527] standard colonoscopy, with polypectomy as indicated, was followed by either indigo carmine chromoendoscopy or repeat “intensive” white-light colonoscopy (a design very nearly identical to the average-risk screening group noted above). In this series, no significant difference in adenoma yield between the chromoendoscopy and intensive white-light groups was detected. However, these patients were younger and in many cases had undergone several previous exams that might have resulted in polyp clearing.
In a German study,[528] one series of Lynch syndrome patients underwent white-light exam followed by chromoendoscopy, while a second series underwent colonoscopy with narrow-band imaging followed by chromoendoscopy. Significant differences in flat polyp detection favored chromoendoscopy in both series, although some of the detected lesions were hyperplastic. In a French series of Lynch syndrome subjects that also employed white-light exam followed by chromoendoscopy, significantly more adenomas were detected with chromoendoscopy.[457]
Fewer evaluations of chromoendoscopy have been performed in AFAP than in Lynch syndrome. One study examined four patients with presumed AFAP and fewer than 20 adenomas upon white-light examination.[529] All had more than 1,000 diminutive adenomas found on chromoendoscopy, in agreement with pathology evaluation after colectomy.
A similar role for chromoendoscopy has been suggested to evaluate the duodenum in FAP. One study from Holland that used indigo carmine dye-spray to detect duodenal adenomas showed an increase in the number and size of adenomas, including some large ones. Overall Spigelman score was not significantly affected.[530]
Small bowel imaging
Patients with PJS and JPS are at greater risk of disease-related complications in the small bowel (e.g., bleeding, obstruction, intussusception, or cancer). FAP patients, although at great risk of duodenal neoplasia, have a relatively low risk of jejunoileal involvement. The RR of small bowel malignancy is very high in Lynch syndrome, but absolute risk is less than 10%. Although the risks of small bowel neoplasia are high enough to warrant consideration of surveillance in each disease, the technical challenges of doing so have been daunting. Because of the technical challenges and relatively low prevalences, there is virtually no evidence base for small-bowel screening in Lynch syndrome.
Historically, the relative endoscopic inaccessibility of the mid and distal small bowel required radiographic measures for its evaluation, including the barium small bowel series or a variant called tube enteroclysis, in which a nasogastroduodenal tube is placed so that all of the contrast goes into the small intestine for more precise imaging. None of these measures were sensitive for small lesions. Any therapeutic undertaking required laparotomy. This entailed resection in most cases, although intraoperative endoscopy, with or without enterotomy for scope access, has been available for many years. Peroral enteroscopy (aided by stiffening overtubes with two balloons, one balloon, or spiral ribs) has been employed to overcome the technical problem of excessive looping, enabling deep jejunal access with therapeutic (polypectomy) potential.
Most data relate that PJS with double-balloon enteroscopy is the preferred method for endoscopy of the small bowel.[531] This may involve only peroral enteroscopy, although subsequent retrograde enteroscopy has been described for more complete evaluation of the total small bowel. Because these procedures are time-consuming and involve some risk of complication, deep enteroscopy is usually preceded by more noninvasive imaging, including traditional barium exams, capsule endoscopy, and CT or magnetic resonance enterography.[83]
In FAP, data from capsule endoscopy [83] show a 50% to 100% prevalence of jejunal and/or ileal polyps in patients with Spigelman stage III or stage IV duodenal involvement but virtually no such polyps in Spigelman stage I or stage II disease. All polyps were smaller than 10 mm and were not biopsied or removed. Consequently, their clinical significance remains uncertain but is likely limited, given the infrequency of jejunoileal cancer reports in FAP.
Capsule endoscopy in the small series of PJS patients described above [83] showed the presence of a similar frequency (50%–100%) of polyps, but the prevalent polyps were much larger than in FAP, were more likely to become symptomatic, and warranted endoscopic or surgical excision. Capsule studies were suggested as an appropriate replacement for radiographic studies because of the sensitivity of capsule endoscopy.
Familial CRC
An estimated 7% to 10% of people have an FDR with CRC,[532,533] and approximately twice that many have either an FDR or a second-degree relative with CRC.[533,534] A simple family history of CRC (defined as one or more close relatives with CRC in the absence of a known hereditary colon cancer) confers a twofold to sixfold increase in risk. The risk associated with family history varies greatly according to the age of onset of CRC in the family members, the number of affected relatives, the closeness of the genetic relationship (e.g., FDRs), and whether cancers have occurred across generations.[532,535] A positive family history of CRC appears to increase the risk of CRC earlier in life such that at age 45 years, the annual incidence is more than three times higher than that in average-risk people; at age 70 years, the risk is similar to that in average-risk individuals.[532] The incidence in a 35- to 40-year-old is about the same as that of an average-risk person at age 50 years. There is no evidence to suggest that CRC in people with one affected FDR is more likely to be proximal or is more rapidly progressive.
A personal history of adenomatous polyps confers a 15% to 20% risk of subsequently developing polyps [536] and increases the risk of CRC in relatives.[537] The RR of CRC, adjusted for sex and the year of birth, was 1.78 (95% CI, 1.18–2.67) for the parents and siblings of the patients with adenomas as compared with the spouse controls. The RR for siblings of patients in whom adenomas were diagnosed before age 60 years was 2.59 (95% CI, 1.46–4.58), compared with the siblings of patients who were 60 years or older at the time of diagnosis and after adjustment for the sibling's year of birth and sex, with a parental history of CRC.
While familial clusters account for approximately 20% of all CRC cases in developed countries,[538] the rare and highly penetrant Mendelian CRC diseases contribute to only a fraction of familial cases, which suggests that other genes and/or shared environmental factors may contribute to the remainder of the cancers. Two studies attempted to determine the degree to which hereditary factors contribute to familial CRCs.
The first study utilized the Swedish, Danish, and Finnish twin registries that cumulatively provided 44,788 pairs of same-sex twins (for men: 7,231 monozygotic [MZ] and 13,769 dizygotic [DZ] pairs; for women: 8,437 MZ and 15,351 DZ pairs) to study the contribution of heritable and environmental factors involved in 11 different cancers.[539] The twins included in the study all resided in their respective countries of origin into adulthood (>50 y). Cancers were identified through their respective national cancer registries in 10,803 individuals from 9,512 pairs of twins. The premise of the study was based on the fact that MZ twins share 100% and DZ twins share 50% of their genes on average for any individual twin pair. This study calculated that heritable factors accounted for 35%, shared environmental factors for 5%, and nonshared environmental factors for 60% of the risk of CRC. For CRC, the estimated heritability was only slightly greater in younger groups than in older groups. This study revealed that although nonshared environmental factors constitute the major risk of familial CRC, heredity plays a larger-than-expected role.
The second study utilized the Swedish Family-Cancer Database, which contained 6,773 CRCs in offspring and 31,100 CRCs in their parents, from 1991 to 2000.[540] The database included 253,467 pairs of spouses, who were married and lived together for at least 30 years, and who were used to control for common environmental effects on cancer risk. In the offspring of an affected parent, the overall SIR for cancer of the colon was 1.81 (95% CI, 1.62–2.02), for cancer of the rectum it was 1.74 (95% CI, 1.53–1.96), and for cancer of the colon-and-rectum combined it was 1.78 (95% CI, 1.53–1.96). The risk conferred by affected siblings was also significantly elevated. Because there was no significantly increased risk of CRC conferred between spouses, the authors concluded that heredity plays a significant role in familial CRCs; however, controls for shared environmental effects among siblings were absent in this study.
Ten percent to 15% of persons with CRC and/or colorectal adenomas have other affected family members,[532,533,535-537,541-546] but their findings do not fit the criteria for FAP, and their family histories may or may not meet clinical criteria for Lynch syndrome. Such families are categorized as having familial CRC, which is currently a diagnosis of exclusion (of known hereditary CRC disorders). The presence of CRC in more than one family member may be caused by hereditary factors, shared environmental risk factors, or even chance. Because of this etiologic heterogeneity, understanding the basis of familial CRC remains a research challenge.
Genetic studies have demonstrated a common autosomal dominant inheritance pattern for colon tumors, adenomas, and cancers in familial CRC families,[547] with a gene frequency of 0.19 for adenomas and colorectal adenocarcinomas.[546] A subset of families with MSI-negative familial colorectal neoplasia was found to link to chromosome 9q22.2-31.2.[548] A more recent study has linked three potential loci in familial CRC families on chromosomes 11, 14, and 22.[549]
Familial colorectal cancer type X (FCCX)
Families meeting Amsterdam-I criteria for Lynch syndrome who do not show evidence of defective MMR by MSI testing do not appear to have the same risk of colorectal or other cancers as those families with classic Lynch syndrome and clear evidence of defective MMR. These Amsterdam-I criteria families with intact MMR systems have been described as FCCX,[251,550-554] and it has been suggested that these families be classified as a distinct group.
The genetic etiology of FCCX remains unclear. Utilizing whole-genome linkage analysis and exome sequencing, a truncating variant in ribosomal protein S20 (RPS20), a ribosomal protein gene, was identified in four individuals with CRC from an FCCX family.[554] The variant cosegregated with CRC in the family, with a logarithm of the odds score of 3. Additionally, the variant was not identified in 292 controls. No LOH was observed in tumor samples, and in vitro analyses of mature RNA formation confirmed a model of haploinsufficiency for RPS20. No germline variants in RPS20 were found in 25 additional FCCX families studied, suggesting RPS20 variants are an infrequent cause of FCCX. The same group had previously identified variants in the bone morphogenetic protein receptor type 1A (BMPR1A) gene in affected individuals from 2 of 18 families with FCCX.[555] Additional studies are necessary to definitively confirm or refute a role for RPS20 or BMPR1A in FCCX.
Age of CRC onset in Lynch syndrome ranges from 44 years (registry series) to a mean of 52 years (population-based series).[255,303,351] There are no corresponding population-based data for FCCX because FCCX by definition requires at least one early-onset case and is not likely to lend itself to any population-based figures in the foreseeable future. Studies that have directly compared age of onset between FCCX and Lynch syndrome have suggested that the age of onset is slightly older in FCCX,[251,550,552] but the lifetime risk of cancer is substantially lower. The SIR for CRC among families with intact MMR (FCCX families) was 2.3 (95% CI, 1.7–3.0) in one large study, compared with 6.1 (95% CI, 5.7–7.2) in families with defective MMR (Lynch syndrome families).[251] The risk of extracolonic tumors was also not found to be elevated in the FCCX families, suggesting that enhanced surveillance for CRC was sufficient. Although further studies are required, tumors arising within FCCX families also appear to have a different pathologic phenotype, with fewer tumor-infiltrating lymphocytes than those in families with Lynch syndrome.[551]
Interventions for family history of CRC
There are no controlled comparisons of screening in people with a mild or modest family history of CRC. Most experts who accept that average-risk people should be screened starting at age 50 years suggest that screening should begin earlier in life (e.g., at age 35–40 y) when the magnitude of risk is comparable to that of a 50-year-old. Because the risk increases with the extent of family history, there is room for clinical judgment in favor of even earlier screening, depending on the details of the family history. Some experts suggest shortening the frequency of the screening interval to every 5 years, rather than every 10 years.[147]
A common but unproven clinical practice is to initiate CRC screening 10 years before the age of the youngest CRC case in the family. There is neither direct evidence nor a strong rational argument for using aggressive screening methods simply because of a modest family history of CRC.
These issues were weighed by a panel of experts convened by the American Gastroenterological Association before publishing clinical guidelines for CRC screening, including those for persons with a positive family history of CRC.[556] These guidelines have been endorsed by a number of other organizations.
The American Cancer Society and the United States Multi-Society Task Force on Colorectal Cancer have published guidelines for average-risk individuals.[147,557-560] These guidelines address screening issues related to modest family history of CRC or adenomas. Given the heterogeneity of this group, it is beyond the scope of this more targeted discussion of major gene conditions.
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