Genetics of Colorectal Cancer (PDQ®)–Health Professional Version
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.[314,315] 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.[267,314,316-319] 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.[320,121,321-323]
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.[324,325] 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.[267] 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%.[326] 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;[327] (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.[326] 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.[328] 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.[329]
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.)
Clinicians are increasingly utilizing tumor sequencing to advance therapeutic decisions in a more personalized approach, particularly in patients with metastatic disease. The performance of next-generation tumor sequencing (NGS) of CRCs for the detection of Lynch syndrome was compared with existing screening protocols that include MSI testing and IHC staining (with BRAF p.V600E testing) in 419 CRC cases recruited in a multicenter, population-based study.[330] Twelve participants were identified as Lynch syndrome carriers by germline DNA testing and all were correctly identified by tumor sequencing, while MSI plus BRAF testing and IHC plus BRAF testing missed five and six Lynch syndrome cases, respectively. Tumor sequencing had a higher sensitivity than IHC plus BRAF testing (100% vs. 89.7%; P = .04) and MSI plus BRAF testing (100% vs. 91.4%; P = .07) while specificity was comparable across all strategies (95.3% for tumor sequencing, 94.6% for IHC plus BRAF, and 94.8% for MSI plus BRAF; P = not significant). In a validation cohort of 46 known Lynch syndrome pathogenic variant carriers with CRC, tumor sequencing yielded similar results and correctly identified 100% of carriers. In addition, the authors highlighted potential therapeutic implications by reporting on somatic alterations identified by tumor sequencing in 283 participants. This study suggested that tumor sequencing is a highly effective mode of identifying Lynch syndrome; however, the cost-effectiveness of this strategy remains to be determined.
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 .[315] 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 BRAF pathogenic 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.[325]
NCCN 2019 guidelines support universal screening of all CRCs with IHC and/or MSI, and/or a comprehensive tumor NGS panel or germline multigene (panel) testing.[121] 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.[315] 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.[315] 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.[331] 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).[332] 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.[333] 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.[315]
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.[334] 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.[335]
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.[336] 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.[337] 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.[338]
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.[339] 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.[337]
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.[335]
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.[340,341] 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 NGS, and two cases (0.8%) with otherwise unexplained MMR-deficiency.[342] 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.[343] 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.[344] 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, a comprehensive tumor NGS panel, or germline multigene (panel) testing of all endometrial cancers.[121] 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.)
MSI in all cancers
Use of MSI testing across all tumor types has become an important screening tool to select cases that may have a favorable response to immune checkpoint inhibitor therapy. These results may potentially be used to screen for Lynch syndrome in tumors other than CRC. A study evaluated MSI across a wide variety of malignancies and evaluated its use as a potential means to identify Lynch syndrome, regardless of tumor type.[345] In a study of more than 15,000 patients with more than 50 types of cancers evaluated in a single-center study, data on well-annotated tumor and matched normal DNA sequencing results with paired germline MMR gene testing, were used to determine MSI status. MSI was determined using a software tool that reports the percentage of unstable microsatellites as a score from paired tumor-normal genome sequencing data and allows for comprehensive investigation of MSI sites simultaneously. The approach used has been reported to be more sensitive across cancers not typically screened for MMR-deficiency (dMMR) than MSI testing of five mononucleotide microsatellite foci using PCR.[346] CRC and endometrial cancer comprised the majority of cancers with MSI-H in this study, but 38% (125 of 326) of MSI-H tumors and more than 90% of those with intermediate-level MSI were other cancer types. Germline testing confirmed a diagnosis of Lynch syndrome in 16.3% and 1.9% of tumors with MSI-H and intermediate-level MSI, respectively, in addition to 0.3% of cases that lacked MSI. Importantly, half of all Lynch syndrome carriers with MSI-H/intermediate tumors had primary cancers other than CRC or endometrial cancer, with many malignancies not associated with Lynch syndrome. Among those individuals with a noncanonical Lynch syndrome cancer, nearly half failed to meet clinical criteria for Lynch syndrome testing on the basis of their cancer diagnosis or family cancer history. Furthermore, intermediate-level MSI and MSS phenotypes were most often observed in cancers not classically related to Lynch syndrome and in individuals with germline PMS2 variants. This study supports other findings related to the variable phenotypic expression of Lynch syndrome on the basis of the altered MMR gene and its broad constellation of associated malignancies that make it difficult to be identified by clinical criteria alone. In addition, the investigators further analyzed a unique gene variant signature in every tumor and correlated results to the observed MSI phenotype and germline MMR status to provide some indirect data on whether a gene variant carrier’s cancer was caused by Lynch syndrome and MMR deficiency or possibly an incidental finding. This is pertinent in evaluating those cancers whose association with Lynch syndrome is unclear and debatable, such as breast and prostate cancer. The authors’ finding that none of the breast cancer patients with Lynch syndrome in this very large cohort had tumors with MSI lends support to the hypothesis that these individuals’ germline MMR gene variants may simply be incidental findings and not etiologic to their cancer diagnosis.
Germline genetic testing
Genetic testing for germline pathogenic variants in MLH1, MSH2, MSH6, PMS2, and EPCAM can 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 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 mutations 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 mutations 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 [347] 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.[348]
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%).[347] 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.[349] 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.[350] 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%).[350] 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).[351] 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.[350] Given the increased prevalence of breast and ovarian cancers, 58.9% met the NCCN guidelines for BRCA1/BRCA2 testing 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.[352] 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.[352]
A 2015 study evaluated the cost-effectiveness of multigene testing for CRC and polyposis syndromes in patients referred to a cancer genetics clinic.[353] 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;[354,355] MSH2 (mutS homolog 2) on chromosome 2p22-21;[356,357] MSH6 on chromosome 2p16;[358] and PMS2 (postmeiotic segregation 2) on chromosome 7p22.[354-357,359-362] 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.[363,364]
Lynch syndrome accounts for about 3% of all newly diagnosed cases of CRC.[314] 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 [267,314,365] versus 71 years in sporadic CRC.[366] 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.[367]
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.[368]
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.[347]
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 MSH6 and PMS2 pathogenic variants has been increasing with improved DNA mutational analyses and universal tumor screening of all CRCs.[368] MSH6 and PMS2 variants may be more common in unselected cases of CRC (and endometrial cancer),[368] compared with MLH1 and MSH2 variants which were more commonly identified in individuals from high-risk CRC clinics.[369,370] A series of papers from the Prospective Lynch Syndrome Database (PLSD) describe the cancer outcomes in patients prospectively followed by (mainly European) registries. Among the key findings was a low risk of CRC in PMS2 carriers, especially among those below age 50 years, leading the authors to conclude that surveillance in PMS2 carriers could safely be scaled back. A later initiation of colonoscopy and perhaps at longer intervals, is gradually being adopted in light of these findings.[121,176] The relative risk of extracolonic cancers in PMS2 carriers was no greater or only slightly greater than population expectations, which led the authors to generally recommend against any extracolonic surveillance in PMS2 carriers.[371] These data in aggregate support a more liberalized approach for screening PMS2 carriers, although current clinical practice guidelines do not reflect this change.[121,176] The approach to screening individuals with PMS2 pathogenic variants, and to a lesser extent those with MSH6 pathogenic variants, are matters of ongoing clinical debate.
MLH1
In early studies, the prevalence of MLH1 pathogenic variants in individuals with Lynch syndrome was reported to be between 41.7% [372] and 50%,[373] 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.[368]
MLH1 pathogenic variants are associated with the entire spectrum of malignancies associated with Lynch syndrome.[373] 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.[295] The highest risk among carriers of pathogenic MLH1 variants is for CRC, which is estimated to be between 41% and 68%,[3,4,367] and the mean age at diagnosis of CRC was 42.8 years (range, 16–81 y) in one study that included 137 affected individuals.[374] 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).[269,375] 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,[372] 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;[368] 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.[295] The lifetime risk of colon cancer associated with MSH2 pathogenic variants is estimated to be between 48% and 68%.[3,4,367] 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).[376] 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.[374]
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%.[358,377-382] The reported prevalence of MSH6 pathogenic variants in the InSiGHT database was 18% in 2012.[372] 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.[377] 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 MSH6 pathogenic variants was estimated to be 1 in 758, ranking as the second most prevalent of the MMR genes following PMS2.[368]
The lifetime risk of any Lynch syndrome–associated cancer among MSH6 pathogenic variant carriers is approximately 25% [295] 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.[383]
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 MSH6 carriers 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 [384] 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%,[267,385] with an increase to 7.5% as reported in the InSiGHT database in 2012.[372] 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.[386] Results from a large, population-based CRC cohort found that the prevalence of PMS2 pathogenic variants was the highest among all MMR variants, in which 1 person in 714 carried a pathogenic PMS2 gene variant.[368]
The lifetime risk of any cancer has been found to range between 25% and 32% for heterozygous PMS2 pathogenic variant carriers.[295] 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%.[387] 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.[388] In addition, patients with PMS2 pathogenic variants presented with CRC 7 to 8 years later than did those with MLH1 and MSH2 pathogenic variants.[385] 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.[371] 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.
The PLSD is a major ongoing initiative to assess cancer risks in Lynch syndrome. Although it lacks specific details regarding screening practices, it includes outcome data from many European programs, classified by age, gender, and MMR gene.[5,389,390] Recognizing limitations in the larger PLSD, a subset with more detailed surveillance data has been provided.[391] These prospective colonoscopy data from Germany, Holland, and Finland included 2,747 patients of whom 62 had no prior cancer at surveillance initiation. Because of differences in surveillance practices, the colonoscopy interval approximated 1 year in Germany, 2 years in Holland, and 3 years in Finland. The median number of colonoscopies was five and the median per-patient observation time was approximately 8 years. Despite the differences in surveillance intervals, similar adenoma detection rates were found in those patients with a history of cancer (14%) and those without (15.6%). At 10 years of follow-up, rates of first cancer were 8.4% and 14% for metachronous tumors. Factors increasing risk were male gender, prior CRC, presence of MLH1 or MSH2 pathogenic variants, age older than 40 years, and adenoma at index colonoscopy. Notably, no significant difference in CRC detection or in stage at detection was noted between screening intervals of 1, 2, or 3 years.
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 syndrome section of this summary for more information.)
The lifetime risk of CRC and endometrial cancer in carriers of these pathogenic variants is summarized in Table 11.
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.[392] 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.[393] 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.[393] 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.[394]
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.[394] However, a subsequent study demonstrated that women with MSH2 protein expression loss caused by EPCAM variants are also at risk of endometrial cancer.[393]
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.[395]
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.[396,397] 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,[398] Portugal, France, Spain, and Hungary, and are likely present in all ethnic groups. Fewer such reports have come from Asia,[399] 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.[400]
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.[401]
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.[402] 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.[403]
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.[404] 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.[347] 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.[348]
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.[405] 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.[406] 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 MLH1 carriers, 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.[389]
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.[407] There is some evidence that the rate of individual cancers varies from kindred to kindred.[408-410]
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.[411]
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.[6,271,367,375,412] 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 MSH2 pathogenic variants.[383] In carriers of PMS2 pathogenic variants, the endometrial cancer risk at age 70 years has been reported to be 15%.[387] 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.[413] 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 PMS2 carriers.[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.[393]
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%).[414]
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 MSH6 carriers.[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.[415] 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.[407,408,416-419] In addition, some studies have suggested an association with breast, prostate, and adrenal cortex cancers.[413,417,420-422] 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.[413] 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).[413]
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.[423,424] Pathogenic variants in the MLH1, MSH2, and MSH6 genes have been found in Muir-Torre families with an increased prevalence described among MSH2 carriers.[425-432] 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 MSH2 pathogenic variants compared with two individuals who had MLH1 pathogenic variants (P = .05).[433] 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.[434] (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;[450-453] one of these studies evaluated breast cancer risk in individuals with Lynch syndrome and found that it is not elevated.[453] However, the largest prospective study to date of 446 unaffected carriers of pathogenic variants from the Colon Cancer Family Registry [413] 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).[413] 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).[454] 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 MLH1 carriers but not in carriers of other MMR variants.[455] 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.[456]
A number of subsequent studies have suggested the presence of higher breast cancer risks than previously published,[350,351,457,458] although this has not been consistently observed.[345] 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%.[457] 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 MSH2 pathogenic variants.[351] 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).[350] 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.[458] 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.[459]
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).[420] 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.[460] This risk is possibly increased in those with MSH2 pathogenic variants.[422,460] 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.”[420] 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%).[461] Currently, molecular and epidemiologic evidence supports prostate cancer as one of the Lynch syndrome cancers. As with breast cancer,[460] 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.[421]
Other cancers
Several additional cancers have been found to be associated with Lynch syndrome in some studies, but further investigation is warranted. Table 12 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.[462] 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.[462] 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.[462]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).[462]
- 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.[123,463,464] 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 13 for available colon surveillance recommendations.)
- The adenoma-carcinoma sequence is accelerated.The progression from normal mucosa to adenoma to cancer is accelerated,[465,466] suggesting that screening should be performed at shorter intervals (every 1–2 years) and with colonoscopy.[466-469] It has been demonstrated that carriers of MMR gene pathogenic variants develop detectable adenomas at an earlier age than do noncarriers.[462,462] 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.[466,470] 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.[466] 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 13), 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.[470]
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.[471,472]
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.[473] 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.[474]
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 [388] 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.[384]
While initial data may support different strategies for the initiation and surveillance of CRC and other extracolonic cancers by specific MMR gene alteration,[413] concerns related to (a) the adherence of recommendations overall by the medical community and by affected individuals [475] and (b) limitations related to specific screening modalities [476] have prevented the implementation of gene-specific guidelines until additional data are available.[121]
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.[121] Two studies have examined the use of TVUS in endometrial screening for women with Lynch syndrome.[480,481] 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.[480] 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.[481] 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.[482] 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.[483,484] (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%.[4,367,438-440] 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.[121]
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.[485] 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.[445] 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.[486]
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.[441] 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).[441,487] 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 H. 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.[121]
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%.[4,374,437-439,442] 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.[440]
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.[4,374,438,439,442,443] 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. [449] Another prospective study using data from the Colon Cancer Family Registry reported an SIR of 10.7 with cumulative risk of 0.95%.[413] 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.[488]
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 surveillance for individuals with a family history of urothelial cancer or individuals with MSH2 pathogenic variants (especially males).[121]
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.[489] 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 [490] 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.[491] 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.[492]
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.[435]
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.[406] 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.[493] 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.[406,494] 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.[495] 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.[495]
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.[496] 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%.[454,497] Two retrospectives studies reported a 15% and 18% incidence of metachronous colon cancer after segmental rectal cancer–resection in patients with Lynch syndrome.[498,499] 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.[499]
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.[500] 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.[501]
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 MLH1 hypermethylation or biallelic somatic mutations 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 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,[504] and are even less common in metastatic disease, being present in only 3% to 4% of metastatic cases.[505] 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%).[506] 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).[507] 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.[508] 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 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).[509] 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.[507] 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.[497] The authors additionally reported a favorable 26% pathologic complete response 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 pathologic complete responses 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.[510] 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.[511] This led to the prediction that DNA dMMR tumors may not be fully sensitive to alkylating agents, 5-FU, and platinum-containing drugs.[512-514] 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.[515] 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.[516] Subsequently, ten studies confirmed this, as all failed to show benefit when CRC patients were given 5-FU–based chemotherapy.[510] 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.[517]
Preclinical data suggests the addition of oxaliplatin to 5-FU can overcome the resistance to 5-FU monotherapy seen in MSI-H tumors.[518] 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.[519] 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.[520,521]
Immunotherapy
Tumors that develop via the MSI pathway have more somatic mutations 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.[522] 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 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 mutations than pMMR tumors. Additionally, in this study somatic mutation 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).[523] 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.[524] 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.[307] 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,[525-527] in which a somatic mutation 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 mutations. (Refer to Table 10 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.[307] 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.[263] 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.[263]
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