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Genetics of Colorectal Cancer (PDQ®) 1/6 –Health Professional Version - National Cancer Institute

Genetics of Colorectal Cancer (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute



Genetics of Colorectal Cancer (PDQ®)–Health Professional Version




Executive Summary

This executive summary reviews the topics covered in the PDQ summary on the genetics of colorectal cancer (CRC), with hyperlinks to detailed sections below that describe the evidence on each topic.
  • Inheritance and Risk
    Factors suggestive of a genetic contribution to CRC include the following: (1) a strong family history of CRC and/or polyps; (2) multiple primary cancers in a patient with CRC; (3) the existence of other cancers within the kindred consistent with known syndromes causing an inherited risk of CRC, such as endometrial cancer; and (4) early age at diagnosis of CRC. Hereditary CRC is most commonly inherited in an autosomal dominant pattern, although two syndromes are inherited in an autosomal recessive pattern (MUTYH-associated polyposis and NTHL1).
    At least three validated computer models are available to estimate the probability that an individual affected with cancer carries a pathogenic variant in a mismatch repair (MMR) gene associated with Lynch syndrome, the most common inherited CRC syndrome. These include the MMRpro, MMRpredict, and PREMM5 (PREdiction Model for gene Mutations) prediction models. Individuals with a quantified risk of 2.5% or greater on PREMM5 or 5% or greater on MMRpro and MMRpredict are recommended for genetic evaluation referral and testing.
  • Associated Genes and Syndromes
    Hereditary CRC has two well-described forms: (1) polyposis (including familial adenomatous polyposis [FAP] and attenuated FAP (AFAP), which are caused by pathogenic variants in the APC gene; and MUTYH-associated polyposis, which is caused by pathogenic variants in the MUTYH gene); and (2) Lynch syndrome (often referred to as hereditary nonpolyposis colorectal cancer), which is caused by germline pathogenic variants in DNA MMR genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM. Other CRC syndromes and their associated genes include oligopolyposis (POLE, POLD1), NTHL1, juvenile polyposis syndrome (BMPR1A, SMAD4), Cowden syndrome (PTEN), and Peutz-Jeghers syndrome (STK11). Many of these syndromes are also associated with extracolonic cancers and other manifestations. Serrated polyposis syndrome, which is characterized by the appearance of hyperplastic polyps, appears to have a familial component, but the genetic basis remains unknown. The natural history of some of these syndromes is still being described. Many other families exhibit aggregation of CRC and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial CRC. In addition, most individuals with CRC diagnosed before age 50 years and without a family history of cancer do not have a pathogenic variant associated with an inherited cancer syndrome.
    Genome-wide searches are showing promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including CRCs, but the clinical utility of these findings remains uncertain.
  • Clinical Management
    It is becoming the standard of care at many centers that all individuals with newly diagnosed CRC are evaluated for Lynch syndrome through molecular diagnostic tumor testing assessing MMR deficiency. A universal screening approach to tumor testing is supported, in which all CRC cases are evaluated regardless of age at diagnosis or fulfillment of existing clinical criteria for Lynch syndrome. A more cost-effective approach has been reported whereby all patients aged 70 years or younger with CRC and older patients who meet the revised Bethesda guidelines are tested for Lynch syndrome. Tumor evaluation often begins with immunohistochemistry testing for the expression of the MMR proteins associated with Lynch syndrome or microsatellite instability (MSI) testing, BRAF testing, and MLH1 hypermethylation analyses.
    Colonoscopy for CRC screening and surveillance is commonly performed in individuals with hereditary CRC syndromes and has been associated with improved survival outcomes. For example, surveillance of Lynch syndrome patients with colonoscopy every 1 to 2 years, and in one study up to 3 years, has been shown to reduce CRC incidence and mortality. Extracolonic surveillance is also a mainstay for some hereditary CRC syndromes depending on the other cancers associated with the syndrome. For example, regular endoscopic surveillance of the duodenum in FAP patients has been shown to improve survival.
    Prophylactic surgery (colectomy) has also been shown to improve survival in patients with FAP. The timing and extent of risk-reducing surgery usually depends on the number of polyps, their size, histology, and symptomatology. For patients with Lynch syndrome and a diagnosis of CRC, extended resection is associated with fewer metachronous CRCs and additional surgical procedures for colorectal neoplasia than in patients who undergo segmental resection for CRC. The surgical decision must take into account the age of the patient, comorbidities, clinical stage of the tumor, sphincter function, and the patient’s wishes.
    Chemopreventive agents have also been studied in the management of FAP and Lynch syndrome. In FAP patients, celecoxib and sulindac have been associated with a decrease in polyp size and number. A double-blind, randomized, controlled trial evaluating the efficacy of sulindac plus an epidermal growth factor receptor inhibitor, erlotinib, versus placebo in FAP or AFAP patients with duodenal polyps suggested that erlotinib has the potential to inhibit duodenal polyps in FAP patients. An ongoing trial will determine whether lower doses of erlotinib alone will significantly reduce duodenal polyp burden. Aspirin use (600 mg daily) was shown to have a preventive effect on cancer incidence in Lynch syndrome patients in a large randomized trial; lower doses are being examined in an ongoing study.
    Novel therapies that stimulate the immune system have been evaluated in MMR-deficient tumors, including those related to Lynch syndrome. The dense immune infiltration and cytokine-rich environment in MMR-deficient tumors may improve clinical outcomes. A critical pathway responsible for mediating tumor-induced immune suppression is the programmed cell death-1 (PD-1)–mediated checkpoint pathway. Two phase 2 studies using anti–PD-1 immune checkpoint inhibitors (pembrolizumab and nivolumab) demonstrated favorable outcomes, including progression-free survival, radiographic response rates, and disease control rates in metastatic CRC with MMR deficiency and MSI that had progressed on prior cytotoxic chemotherapy. Pembrolizumab has shown similar benefit in other noncolorectal cancers with MMR deficiency and MSI, but not in tumors that are microsatellite stable.
  • Psychosocial and Behavioral Issues
    Psychosocial factors influence decisions about genetic testing for inherited cancer risk and risk-management strategies. Uptake of genetic counseling and genetic testing for Lynch syndrome and FAP varies widely across studies. Factors that have been associated with genetic counseling and testing uptake in Lynch syndrome families include having children, the number of affected relatives, perceived risk of developing CRC, and frequency of thoughts about CRC. Psychological studies have shown low levels of distress, particularly in the long term, after genetic testing for Lynch syndrome in both carriers and noncarriers. However, other studies have demonstrated the possibility of increased distress following genetic testing for FAP. Colon and gynecologic cancer screening rates have been shown to increase or be maintained among carriers of MMR pathogenic variants within the year after disclosure of results, while screening rates decrease among noncarriers. The latter is expected as the screening recommendations for unaffected individuals are those that apply to the general population. Studies measuring quality-of-life variables in FAP patients show normal-range results; however, these studies suggest that risk-reducing surgery for FAP may have negative quality-of-life effects for at least some proportion of those affected. Patients' communication with their family members about an inherited risk of CRC is complex; gender, age, and the degree of relatedness are some elements that affect disclosure of this information. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.

Introduction



[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]
[Note: Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) catalog. Refer to OMIMExit Disclaimer for more information.]
[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a genetic difference that exists between the person or group being studied and the reference sequence, particularly for differences that exist in the germline. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women.
Estimated new cases and deaths from CRC in 2019 in the United States:[1]
  • New cases: 145,600.
  • Deaths: 51,020.
About 75% of patients with CRC have sporadic disease with no apparent evidence of having inherited the disorder. The remaining 10% to 30% of patients have a family history of CRC that suggests a hereditary contribution, common exposures or shared risk factors among family members, or a combination of both.[2] Pathogenic variants in high-penetrance genes have been identified as the cause of inherited cancer risk in some colon cancer–prone families; these are estimated to account for only 5% to 6% of CRC cases overall.[3,4]
In addition, pathogenic variants in lower penetrance genes may contribute to familial colon cancer risk. In such cases, gene-gene and gene-environment interactions may contribute to the development of CRC.
(Refer to the PDQ summaries on Colorectal Cancer Screening; Colorectal Cancer Prevention; Colon Cancer Treatment; and Rectal Cancer Treatment for more information about sporadic CRC.)

Colorectal Polyps as Precursors to Colorectal Cancer (CRC)

Colorectal tumors present with a broad spectrum of neoplasms, ranging from benign growths to invasive cancer, and are predominantly epithelial-derived tumors (i.e., adenomas or adenocarcinomas).
Transformation of any polyp into cancer goes through the adenoma-carcinoma sequence. Polyps that have traditionally been considered nonneoplastic include those of the hyperplastic, juvenile, hamartomatous, inflammatory, and lymphoid types. However, in certain circumstances, hamartomatous and juvenile polyps can progress into cancer.
Research, however, does suggest a substantial risk of colon cancer in individuals with juvenile polyposis syndrome and Peutz-Jeghers syndrome, although the nonadenomatous polyps associated with these syndromes have historically been viewed as nonneoplastic.[5-7]
Epidemiologic studies have shown that a personal history of colon adenomas places one at an increased risk of developing colon cancer.[8]
Two complementary interpretations of this observation are as follows:
  1. The adenoma may reflect an innate or acquired tendency of the colon to form tumors.
  2. Adenomas are the primary precursor lesion of colon cancer.
More than 95% of CRCs are carcinomas, and about 95% of these are adenocarcinomas. It is well recognized that adenomatous polyps are benign tumors that may undergo malignant transformation. They have been classified into three histologic types, with increasing malignant potential: tubular, tubulovillous, and villous. Adenocarcinomas are generally considered to arise from adenomas,[9-13] based upon the following important observations:
  1. Benign and malignant tissue occur within colorectal tumors.[14]
  2. When patients with adenomas were followed for 20 years, the risk of cancer at the site of the adenoma was 25%, a rate much higher than that expected in the normal population.[15]
The following three characteristics of adenomas are highly correlated with the potential to transform into cancer:[14]
  1. Larger size.
  2. Villous pathology.
  3. The degree of dysplasia within the adenoma.
In addition, removal of adenomatous polyps is associated with reduced CRC incidence.[16,17] While most adenomas are polypoid, flat and depressed lesions may be more prevalent than previously recognized. Large, flat, and depressed lesions may be more likely to be severely dysplastic, although this remains to be clearly proven.[18,19] Specialized techniques may be needed to identify, biopsy, and remove such lesions.[20]

Family History as a Risk Factor for CRC

Some of the earliest studies of family history of CRC were those of Utah families that reported a higher percentage of deaths from CRC (3.9%) among the first-degree relatives (FDRs) of patients who had died from CRC than among sex-matched and age-matched controls (1.2%).[21] This difference has since been replicated in numerous studies that have consistently found that FDRs of affected cases are themselves at a twofold to threefold increased risk of CRC. Despite the various study designs (case-control, cohort), sampling frames, sample sizes, methods of data verification, analytic methods, and countries where the studies originated, the magnitude of risk is consistent.[22-27]
A systematic review and meta-analysis of familial CRC risk has been reported.[28] Of 24 studies included in the analysis, all but one reported an increased risk of CRC if there was an affected FDR. The relative risk (RR) for CRC in the pooled study was 2.25 (95% confidence interval [CI], 2.00–2.53) if there was an affected FDR. In 8 of 11 studies, if the index cancer arose in the colon, the risk was slightly higher than if it arose in the rectum. The pooled analysis revealed an RR in relatives of colon and rectal cancer patients of 2.42 (95% CI, 2.20–2.65) and 1.89 (95% CI, 1.62–2.21), respectively. The analysis did not reveal a difference in RR for colon cancer based on location of the tumor (right side vs. left side).
The number of affected family members and age at cancer diagnosis correlated with the CRC risk. In studies reporting more than one FDR with CRC, the RR was 3.76 (95% CI, 2.56–5.51). The highest RR was observed when the index case was diagnosed in individuals younger than 45 years (RR, 3.87; 95% CI, 2.40–6.22) compared with family members of index cases diagnosed at ages 45 to 59 years (RR, 2.25; 95% CI, 1.85–2.72), and to family members of index cases diagnosed at age 60 years or older (RR, 1.82; 95% CI, 1.47–2.25). In this meta-analysis, the familial risk of CRC associated with adenoma in an FDR was analyzed. The pooled analysis demonstrated an RR for CRC of 1.99 (95% CI, 1.55–2.55) in individuals who had an FDR with an adenoma.[28] This finding has been corroborated.[29] Other studies have reported that age at diagnosis of the adenoma influences the CRC risk, with younger age at adenoma diagnosis associated with higher RR.[30,31] As with any meta-analysis, there could be potential biases that might affect the results of the analysis, including incomplete and nonrandom ascertainment of studies included; publication bias; and heterogeneity between studies relative to design, target populations, and control selection. This study is reinforcement that there are significant associations between familial CRC risk, age at diagnosis of both CRC and adenomas, and multiplicity of affected family members.
Table 1. Estimated Relative and Absolute Risk of Developing Colorectal Cancer (CRC)
Family HistoryRelative Risk of CRC [28]Absolute Risk (%) of CRC by Age 79 ya
CI = confidence interval; FDR = first-degree relative.
aData from the Surveillance, Epidemiology, and End Results database.
bThe absolute risks of CRC for individuals with affected relatives was calculated using the relative risks for CRC [28] and the absolute risk of CRC by age 79 yearsa.
No family history14a
One FDR with CRC2.3 (95% CI, 2.0–2.5)9b
More than one FDR with CRC4.3 (95% CI, 3.0–6.1)16b
One affected FDR diagnosed with CRC before age 45 y3.9 (95% CI, 2.4–6.2)15b
One FDR with colorectal adenoma2.0 (95% CI, 1.6–2.6)8b
When the family history includes two or more relatives with CRC, the possibility of a genetic syndrome is increased substantially. The first step in this evaluation is a detailed review of the family history to determine the number of relatives affected, their relationship to each other, the age at which the CRC was diagnosed, the presence of multiple primary CRCs, and the presence of any other cancers (e.g., endometrial) consistent with an inherited CRC syndrome. (Refer to the Major Genetic Syndromes section of this summary for more information.) Computer models are now available to estimate the probability of developing CRC.[32] These models can be helpful in providing genetic counseling to individuals at average risk and high risk of developing cancer. In addition, at least three validated models are also available for predicting the probability of carrying a pathogenic variant in a mismatch repair (MMR) gene.[33-35]
Figure 1 shows the proportion of CRC cases that arise in various family risk settings.[36]
ENLARGEPie chart showing the fractions of colon cancer cases that arise in various family risk settings. The majority of colon cancer cases diagnosed in these settings are sporadic. The remaining cancer cases are: cases with familial risk (10%–30%); Lynch syndrome (hereditary nonpolyposis colorectal cancer) (2%–3%); familial adenomatous polyposis (<1%); and hamartomatous polyposis syndrome (<0.1%).
Figure 1. The fractions of colon cancer cases that arise in various family risk settings. Reprinted from Gastroenterology, Vol. 119, No. 3, Randall W. Burt, Colon Cancer Screening, Pages 837-853, Copyright (2000), with permission from Elsevier.

Inheritance of CRC Predisposition

Several genes associated with CRC risk have been identified; these are described in detail in the Colon Cancer Genes section of this summary. Almost all pathogenic variants known to cause a predisposition to CRC are inherited in an autosomal dominant fashion.[37] One example of autosomal recessive inheritance, MUTYH-associated polyposis (MAP), has been identified. (Refer to the MUTYH-Associated Polyposis [MAP] section of this summary for more information.) Thus, the family characteristics that suggest autosomal dominant inheritance of cancer predisposition are important indicators of high risk and of the possible presence of a cancer-predisposing pathogenic variant. These include the following:
  1. Vertical transmission of cancer predisposition in autosomal dominant conditions. (Vertical transmission refers to the presence of a genetic predisposition in sequential generations.)
  2. Inheritance risk of 50% for both male and female children. When a parent carries an autosomal dominant genetic predisposition, each child has a 50% chance of inheriting the predisposition. The risk is the same for both male and female children.
  3. Other clinical characteristics also suggest the presence of a hereditary CRC syndrome:
    • Cancers in people with a hereditary predisposition typically occur at an earlier age than in sporadic cases.[38]
    • A predisposition to CRC may include a predisposition to other cancers, such as endometrial cancer, as detailed in the Major Genetic Syndromes section of this summary.
    • In addition, two or more primary cancers may occur in a single individual. These could be multiple primary cancers of the same type (e.g., two separate primary CRCs) or primary cancer of different types (e.g., colorectal and endometrial cancer in the same individual).
    • The presence of nonneoplastic extracolonic features may suggest a hereditary colon cancer predisposition syndrome (e.g., congenital hypertrophy of the retinal pigment epithelium and desmoid tumors in familial adenomatous polyposis [FAP]).
    • An uncommon tumor (e.g., adrenocortical carcinoma, sebaceous adenoma or carcinoma, and trichilemmoma) may serve as a clue to the presence of a hereditary cancer syndrome.
    • The presence of multiple polyps may suggest a hereditary colon cancer predisposition syndrome. As susceptibility to oligopolyposis (as few as 10–15 polyps) has become apparent, clinicians, and gastrointestinal endoscopists in particular, may consider multigene (panel) testing of an ever-expanding list of genes associated with CRC. (Refer to Table 2, Genes Associated with a High Susceptibility of Colorectal Cancer, for more information.) Because oligopolyposis also involves diverse pathology (including hamartomas, sessile serrated polyps, and sessile serrated adenomas), careful attention to polyp count and polyp histologies helps to determine whether genetic testing and/or further clinical evaluation is appropriate.
The two most common causes of hereditary CRC are FAP (including AFAP), due to germline pathogenic variants in the APC gene,[39-46] and Lynch syndrome (previously called hereditary nonpolyposis colorectal cancer [HNPCC]), which is caused by germline pathogenic variants in DNA MMR genes.[47-50] (Figure 2 depicts a classic family with Lynch syndrome, highlighting some of the indicators of hereditary CRC that are described above.) Many other families exhibit aggregation of CRC and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial CRC.[37]
ENLARGEPedigree showing some of the classic features of a family with Lynch syndrome across three generations, including transmission occurring through maternal and paternal lineages and the presence of both colon and endometrial cancers.
Figure 2. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer, a young age at onset in some individuals, and incomplete penetrance. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure. Because the cancer risk is not 100%, individuals who have Lynch syndrome may not develop cancer, such as the mother of the female with colon cancer diagnosed at age 37 years in this pedigree (called incomplete penetrance).

Identification of Persons at High Genetic Risk of CRC

Guidelines have been developed by the American College of Medical Genetics and the National Society of Genetic Counselors to aid in the identification of patients appropriate for referral to a cancer genetic counseling service.[51]
When such persons are identified, options tailored to the patient situation are considered. (Refer to the Major Genetic Syndromes section of this summary for information on specific interventions for individual syndromes.)
At this time, the use of pathogenic variant testing to identify genetic susceptibility to CRC is not recommended as a screening measure in the general population. The rarity of pathogenic variants in CRC-associated genes and the limited sensitivity of current testing strategies render general population testing potentially misleading and not cost-effective.
Rather detailed recommendations for surveillance in FAP and Lynch syndrome have been provided by several organizations representing various medical specialties and societies. These organizations include the following:
The evidence bases for recommendations are generally included within the statements or guidelines. In many instances, these guidelines reflect expert opinion resting on studies that are rarely randomized prospective trials.

Difficulties in Identifying a Family History of CRC Risk

The accuracy and completeness of family history data must be taken into account in using family history to assess individual risk in clinical practice, and in identifying families appropriate for cancer research. A reported family history may be erroneous, or a person may be unaware of relatives with cancer.[57] Increased use of colonoscopy may result in fewer CRCs and more precancerous colon polyps in a family history. Individuals are much less likely to know about their family history of polyps (i.e., type of polyps and total number of polyps in their relatives) than they are to know about their family history of cancer. In addition, small family sizes and premature deaths may limit how informative a family history may be. Also, due to incomplete penetrance, some persons may carry a genetic predisposition to CRC but do not develop cancer, giving the impression of skipped generations in a family tree.
Accuracy of patient-reported family history of colon cancer has been shown to be good, but it is not optimal. Patient report should be verified by obtaining medical records whenever possible, especially for reproductive tract cancers that may be relevant in identifying risk of Lynch syndrome and less reliably reported by some patients. (Refer to the Accuracy of the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Several approaches are available to evaluate a patient with newly diagnosed CRC who may or may not be suspected of having a cancer genetics syndrome. The clinician may suspect a potential inherited disposition based on the family history and physical exam, and genetic tests are available to confirm these suspicions. The American College of Medical Genetics and Genomics has published guidelines for evaluating patients with suspected colon cancer susceptibility syndromes.[51] The guidelines aim to identify individuals whose clinical features warrant referral for genetics consultation. If an individual has multiple polyps (>20), depending on the histology, specific gene-directed testing can be a useful diagnostic tool. Similarly, if a patient’s clinical presentation is suspicious for Lynch syndrome, germline genetic testing can be directed towards this syndrome. However, diagnosis is more challenging when the clinical picture is less clear. Currently, tumor screening for Lynch syndrome is the most commonly accepted approach. However, increasingly, panels characterizing somatic mutations in tumors are being utilized for a variety of clinical decisions.
A priori risk-assessment testing (which models risk based on a variety of factors, such as age at cancer onset and the spectrum of tumors in the family) may be an appropriate alternative in many cases. Application of such risk models does anticipate the use of multigene (panel) testing; however, their exact role remains to be established.

Molecular Events Associated With Colon Carcinogenesis

Much of our initial understanding of the molecular pathogenesis of CRC derived from rare hereditary CRC syndromes and revealed heterogeneity of CRC both molecularly and clinically. It is well accepted that most CRCs develop from adenomas. The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.[58-60] Presently, CRC can be separated into three categories based on similar molecular genetic features, suggesting divergent pathways of tumorigenesis: chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). The understanding of the molecular genetic pathways of colorectal tumorigenesis is still evolving, and each new level of understanding has occurred in the context of the preceding level of knowledge. In addition, these pathways emerged from important clinical and histological heterogeneity of colorectal polyps and cancers. Thus, the introduction below captures the chronological evolution of our current understanding of colorectal tumorigenesis.

Chromosomal instability (CIN) pathway

The majority of CRCs develop through the CIN pathway. Key changes in CIN cancers include widespread alterations in chromosome number (aneuploidy) and frequent detectable losses at the molecular level of portions of chromosomes (loss of heterozygosity), such as 5q, 18q, and 17p; and pathogenic variants of the KRAS oncogene. The important genes involved in these chromosome losses are APC (5q), DCC/MADH2/MADH4 (18q), and TP53 (17p).[59,61] These chromosomal losses are indicative of genetic instability at the molecular and chromosomal levels.[60] Among the earliest and most common events in the colorectal tumor progression pathway is loss or pathogenic variant–inactivation of the APC gene. Pathogenic variant–inactivation of APC was first shown to be important to CRC in FAP, a hereditary CRC syndrome in which affected individuals harbor germline APC alterations, resulting in its loss of function and a dramatically increased incidence of colorectal polyps and cancers. Acquired or inherited pathogenic variants of DNA damage-repair genes, for example, base excision repair, nucleotide excision repair, double stranded repair, and MMR, also play a role in predisposing colorectal epithelial cells to pathogenic variants.

Microsatellite instability (MSI) pathway

Soon thereafter, a subset (10%–15%) of CRCs was identified that lacked evidence of chromosomal instability but exhibited aberrations in microsatellite repeat sequences,[62,63] a characteristic of tumors in patients with Lynch syndrome.[64] It was later found that hypermethylation of the MLH1 promoter is responsible for sporadic CRCs with MSI. Germline variants in DNA MMR genes were discovered in Lynch syndrome patients, whose CRCs frequently displayed MSI. Thus, the microsatellite instability pathway (MSI, sometimes referred to as MIN) was proposed.
The key characteristics of MSI cancers are that they have a largely intact chromosome complement and, as a result of defects in the DNA MMR system, more readily acquire pathogenic variants in important and often unique cancer-associated genes. These types of cancers are detectable at the molecular level by alterations in repeating units of DNA that occur normally throughout the genome, known as DNA microsatellites.
The rate of adenoma-to-carcinoma progression appears to be faster in microsatellite-unstable tumors than in microsatellite-stable tumors.[65] The foundation for this is the repeated reports of interval cancers in patients with recent, normal colonoscopy. Further support for this is seen in the serrated pathway (see below), in which high rates of interval cancer have also been observed.[66,67] Characteristic histologic changes, such as increased mucin production, can be seen in tumors that demonstrate MSI, intratumoral T lymphocyte infiltration/Crohn-like reaction, etc., distinguishing the colorectal tumors in this pathway.
The knowledge derived from the study of inherited CRC syndromes has provided important clues regarding the molecular events that mediate tumor initiation and tumor progression in people without germline abnormalities. Among the earliest events in the colorectal tumor progression pathway (both MSI and CIN) is loss of function of the APC gene product.

CpG island methylator phenotype (CIMP) and the serrated polyposis pathway

Beginning in the 1980s, studies began reporting an increased risk of CRC in patients with hyperplastic polyposis syndrome (HPS), now referred to as serrated polyposis syndrome (SPS).[6,7,68-73] Only a minority of SPS appear to be familial, but no common germline variant has been identified in these families to date. A comparison of the hyperplastic polyps (HPs) found in SPS patients and controls revealed that SPS polyps are histologically distinct and are similar to previously described serrated adenomas, polyps with features of HPs and adenomatous polyps (APs).[74] This led to observations that these sessile serrated adenomas (SSA) tend to occur in the right colon, where they are frequently large and sessile, and exhibit increased proliferation, dilation and serration of the crypt bases, decreased endocrine cells, and lack of dysplasia.[75]
Further histological characterization of serrated polyps led to subtypes: traditional serrated adenomas (TSA), mixed serrated polyps (MP), and more recently, sessile serrated adenoma/sessile serrated polyp (SSA/SSP).[76] TSAs are characterized by a protuberant morphology, ectopic crypt formation (suggestive of deficient bone morphogenetic protein signaling), and villiform and dysplastic histopathology.[75,77] TSAs are not simply SSAs with dysplasia, and evidence that SSAs are precursors of TSAs is lacking. MPs have overlapping features of HPs, SSAs, and TSAs.
In colonoscopy screening studies, large serrated polyps were strongly and independently associated with the development of advanced colorectal neoplasms, while left-sided HPs were not. The term SSA has been a concern to clinicians as these characteristically lack nuclear atypia, the traditional hallmark of adenomas, but rather are termed adenomas due to other architectural features. The classification of SSA is supported by the knowledge that the molecular characteristics denote an increased cancer risk.[74,78,79]
While APs in Lynch syndrome patients can exhibit MSI, sporadic adenomas rarely do. However, serrated polyps with dysplasia can exhibit MSI with hypermethylation of the MLH1 promoter. Large (>1 cm) serrated polyps carry greater cancer risk than do conventional hyperplastic polyps and, when developing into cancers, characteristically exhibit MSI.[77,80-82] In a review of resected serrated polyps with a malignant focus, all of the polyps originated in the right colon and were SSAs.[80] The malignant foci were MSI and demonstrated loss of MLH1 immunoreactivity, suggesting an association between SSAs and sporadic MSI colon cancers.
The MSI seen in sporadic CRCs is due to hypermethylation of the promoter of MLH1, which abrogates its expression. As promoter regions of other tumor suppressor genes were “silenced” through hypermethylation, cancer genome studies of CRC ensued. These showed a consistent pattern of hypermethylation in the evaluated genes in approximately 50% of CRCs.[83] Studies of larger numbers of unselected CRC patients show that a minority of CRCs (20%–30%) demonstrate CIMP, defined as hypermethylation of two or more of the CpG islands in MINT1, MINT2, MINT31, CDKN2A (p16), and MLH1.[84,85] The term CIMP was coined to classify these cancers, which shared clinical features. Early attempts to differentiate CIMP-positive and CIMP-negative CRCs were unsuccessful.[86] However, subsequent studies using unbiased hierarchical cluster analysis of heavily methylated genes in CRCs and a population-based study design successfully identified unique clinical and molecular characteristics supporting a CIMP pathway.[83,87]
CIMP-high CRCs were much more likely (82.1%; P < .0001) to express MSI than were microsatellite-stable CRCs (24.4%; P < .0001).[83] In one study, microsatellite-stable, CIMP-high (>2 CIMP markers mentioned above) colorectal tumors were significantly more associated with BRAF V600E variants, KRAS2 variants, proximal site, higher American Joint Committee on Cancer stage, older patient age, poor differentiation, and mucinous histology than were CIMP-low (<2 CIMP markers mentioned above) colorectal tumors.[83] Microsatellite-unstable, CIMP-high colorectal tumors were significantly more associated with BRAF V600E pathogenic variants, proximal site, older patient age, and absence of KRAS2 pathogenic variants than were microsatellite unstable, CIMP-low tumors.[83] There was a significantly greater presence of BRAF V600E pathogenic variants in CIMP-high colorectal tumors regardless of MSI.[83] Thus, unlike a previous study that questioned the biological significance of CIMP once unstable colorectal tumors were excluded,[86] this study demonstrated several clinicopathologic variables were indeed associated with CIMP in microsatellite-stable and microsatellite-unstable colorectal tumors.[83]
Studies of polyps revealed CIMP-positive polyps in HPS patients and most frequently in right-sided SSAs.[67,88-91] More recently, a hotspot BRAF pathogenic variant (V600E) was found to be common in MSI colon cancers and serrated polyps.[92-94] A BRAF pathogenic variant is absent in CRCs from Lynch syndrome patients and is rare in sporadic adenomatous colorectal polyps, but it is present in the vast majority of serrated polyps, especially SSAs.[89,91,95-97] CIMP positivity is commonly found in microvesicular hyperplastic polyps (MVHP), suggesting progression of MVHP to SSA and then to colon cancer.[89]

Conclusion

The characterization of CIMP CRCs and evidence that MSI occurs later in the adenoma-carcinoma sequence leads to modification of the previous colorectal tumorigenesis model, which was comprised of two pathways: MSI (MIN) and CIN. There is much overlap between the MSI and CIMP pathways. At the heart of the CIMP pathway are serrated polyps harboring BRAF pathogenic variants. The CIN pathway is characterized by AP precursors of which the vast majority harbor APC pathogenic variants that occur early in the pathway.

References
  1. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available onlineExit Disclaimer. Last accessed June 7, 2019.
  2. Kanth P, Grimmett J, Champine M, et al.: Hereditary Colorectal Polyposis and Cancer Syndromes: A Primer on Diagnosis and Management. Am J Gastroenterol 112 (10): 1509-1525, 2017. [PUBMED Abstract]
  3. Lynch HT, Smyrk TC, Watson P, et al.: Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 104 (5): 1535-49, 1993. [PUBMED Abstract]
  4. Rustgi AK: The genetics of hereditary colon cancer. Genes Dev 21 (20): 2525-38, 2007. [PUBMED Abstract]
  5. Howe JR, Mitros FA, Summers RW: The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 5 (8): 751-6, 1998. [PUBMED Abstract]
  6. Jeevaratnam P, Cottier DS, Browett PJ, et al.: Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. J Pathol 179 (1): 20-5, 1996. [PUBMED Abstract]
  7. Rashid A, Houlihan PS, Booker S, et al.: Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology 119 (2): 323-32, 2000. [PUBMED Abstract]
  8. Neugut AI, Jacobson JS, DeVivo I: Epidemiology of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev 2 (2): 159-76, 1993 Mar-Apr. [PUBMED Abstract]
  9. Shinya H, Wolff WI: Morphology, anatomic distribution and cancer potential of colonic polyps. Ann Surg 190 (6): 679-83, 1979. [PUBMED Abstract]
  10. Fenoglio CM, Lane N: The anatomical precursor of colorectal carcinoma. Cancer 34 (3): suppl:819-23, 1974. [PUBMED Abstract]
  11. Morson B: President's address. The polyp-cancer sequence in the large bowel. Proc R Soc Med 67 (6): 451-7, 1974. [PUBMED Abstract]
  12. Muto T, Bussey HJ, Morson BC: The evolution of cancer of the colon and rectum. Cancer 36 (6): 2251-70, 1975. [PUBMED Abstract]
  13. Stryker SJ, Wolff BG, Culp CE, et al.: Natural history of untreated colonic polyps. Gastroenterology 93 (5): 1009-13, 1987. [PUBMED Abstract]
  14. O'Brien MJ, Winawer SJ, Zauber AG, et al.: The National Polyp Study. Patient and polyp characteristics associated with high-grade dysplasia in colorectal adenomas. Gastroenterology 98 (2): 371-9, 1990. [PUBMED Abstract]
  15. Winawer SJ, Stewart ET, Zauber AG, et al.: A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. National Polyp Study Work Group. N Engl J Med 342 (24): 1766-72, 2000. [PUBMED Abstract]
  16. Winawer SJ, Zauber AG, Ho MN, et al.: Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 329 (27): 1977-81, 1993. [PUBMED Abstract]
  17. Müller AD, Sonnenberg A: Prevention of colorectal cancer by flexible endoscopy and polypectomy. A case-control study of 32,702 veterans. Ann Intern Med 123 (12): 904-10, 1995. [PUBMED Abstract]
  18. O'brien MJ, Winawer SJ, Zauber AG, et al.: Flat adenomas in the National Polyp Study: is there increased risk for high-grade dysplasia initially or during surveillance? Clin Gastroenterol Hepatol 2 (10): 905-11, 2004. [PUBMED Abstract]
  19. Zauber AG, O'Brien MJ, Winawer SJ: On finding flat adenomas: is the search worth the gain? Gastroenterology 122 (3): 839-40, 2002. [PUBMED Abstract]
  20. Rembacken BJ, Fujii T, Cairns A, et al.: Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK. Lancet 355 (9211): 1211-4, 2000. [PUBMED Abstract]
  21. Woolf CM: A genetic study of carcinoma of the large intestine. Am J Hum Genet 10 (1): 42-7, 1958. [PUBMED Abstract]
  22. Fuchs CS, Giovannucci EL, Colditz GA, et al.: A prospective study of family history and the risk of colorectal cancer. N Engl J Med 331 (25): 1669-74, 1994. [PUBMED Abstract]
  23. Slattery ML, Kerber RA: Family history of cancer and colon cancer risk: the Utah Population Database. J Natl Cancer Inst 86 (21): 1618-26, 1994. [PUBMED Abstract]
  24. Negri E, Braga C, La Vecchia C, et al.: Family history of cancer and risk of colorectal cancer in Italy. Br J Cancer 77 (1): 174-9, 1998. [PUBMED Abstract]
  25. St John DJ, McDermott FT, Hopper JL, et al.: Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 118 (10): 785-90, 1993. [PUBMED Abstract]
  26. Duncan JL, Kyle J: Family incidence of carcinoma of the colon and rectum in north-east Scotland. Gut 23 (2): 169-71, 1982. [PUBMED Abstract]
  27. Rozen P, Fireman Z, Figer A, et al.: Family history of colorectal cancer as a marker of potential malignancy within a screening program. Cancer 60 (2): 248-54, 1987. [PUBMED Abstract]
  28. Johns LE, Houlston RS: A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 96 (10): 2992-3003, 2001. [PUBMED Abstract]
  29. Cottet V, Pariente A, Nalet B, et al.: Colonoscopic screening of first-degree relatives of patients with large adenomas: increased risk of colorectal tumors. Gastroenterology 133 (4): 1086-92, 2007. [PUBMED Abstract]
  30. Winawer SJ, Zauber AG, Gerdes H, et al.: Risk of colorectal cancer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med 334 (2): 82-7, 1996. [PUBMED Abstract]
  31. Ahsan H, Neugut AI, Garbowski GC, et al.: Family history of colorectal adenomatous polyps and increased risk for colorectal cancer. Ann Intern Med 128 (11): 900-5, 1998. [PUBMED Abstract]
  32. Win AK, Macinnis RJ, Hopper JL, et al.: Risk prediction models for colorectal cancer: a review. Cancer Epidemiol Biomarkers Prev 21 (3): 398-410, 2012. [PUBMED Abstract]
  33. Chen S, Wang W, Lee S, et al.: Prediction of germline mutations and cancer risk in the Lynch syndrome. JAMA 296 (12): 1479-87, 2006. [PUBMED Abstract]
  34. Balmaña J, Stockwell DH, Steyerberg EW, et al.: Prediction of MLH1 and MSH2 mutations in Lynch syndrome. JAMA 296 (12): 1469-78, 2006. [PUBMED Abstract]
  35. Barnetson RA, Tenesa A, Farrington SM, et al.: Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 354 (26): 2751-63, 2006. [PUBMED Abstract]
  36. Burt RW: Colon cancer screening. Gastroenterology 119 (3): 837-53, 2000. [PUBMED Abstract]
  37. Burt RW, Petersen GM: Familial colorectal cancer: diagnosis and management. In: Young GP, Rozen P, Levin B, eds.: Prevention and Early Detection of Colorectal Cancer. London, England: WB Saunders, 1996, pp 171-194.
  38. Mork ME, You YN, Ying J, et al.: High Prevalence of Hereditary Cancer Syndromes in Adolescents and Young Adults With Colorectal Cancer. J Clin Oncol 33 (31): 3544-9, 2015. [PUBMED Abstract]
  39. Kinzler KW, Nilbert MC, Su LK, et al.: Identification of FAP locus genes from chromosome 5q21. Science 253 (5020): 661-5, 1991. [PUBMED Abstract]
  40. Groden J, Thliveris A, Samowitz W, et al.: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66 (3): 589-600, 1991. [PUBMED Abstract]
  41. Leppert M, Burt R, Hughes JP, et al.: Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med 322 (13): 904-8, 1990. [PUBMED Abstract]
  42. Spirio L, Olschwang S, Groden J, et al.: Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75 (5): 951-7, 1993. [PUBMED Abstract]
  43. Brensinger JD, Laken SJ, Luce MC, et al.: Variable phenotype of familial adenomatous polyposis in pedigrees with 3' mutation in the APC gene. Gut 43 (4): 548-52, 1998. [PUBMED Abstract]
  44. Soravia C, Berk T, Madlensky L, et al.: Genotype-phenotype correlations in attenuated adenomatous polyposis coli. Am J Hum Genet 62 (6): 1290-301, 1998. [PUBMED Abstract]
  45. Pedemonte S, Sciallero S, Gismondi V, et al.: Novel germline APC variants in patients with multiple adenomas. Genes Chromosomes Cancer 22 (4): 257-67, 1998. [PUBMED Abstract]
  46. Sieber OM, Lamlum H, Crabtree MD, et al.: Whole-gene APC deletions cause classical familial adenomatous polyposis, but not attenuated polyposis or "multiple" colorectal adenomas. Proc Natl Acad Sci U S A 99 (5): 2954-8, 2002. [PUBMED Abstract]
  47. Leach FS, Nicolaides NC, Papadopoulos N, et al.: Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75 (6): 1215-25, 1993. [PUBMED Abstract]
  48. Papadopoulos N, Nicolaides NC, Wei YF, et al.: Mutation of a mutL homolog in hereditary colon cancer. Science 263 (5153): 1625-9, 1994. [PUBMED Abstract]
  49. Nicolaides NC, Papadopoulos N, Liu B, et al.: Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371 (6492): 75-80, 1994. [PUBMED Abstract]
  50. Miyaki M, Konishi M, Tanaka K, et al.: Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet 17 (3): 271-2, 1997. [PUBMED Abstract]
  51. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
  52. Smith RA, Cokkinides V, Eyre HJ: American Cancer Society guidelines for the early detection of cancer, 2006. CA Cancer J Clin 56 (1): 11-25; quiz 49-50, 2006 Jan-Feb. [PUBMED Abstract]
  53. Winawer S, Fletcher R, Rex D, et al.: Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 124 (2): 544-60, 2003. [PUBMED Abstract]
  54. Church J, Simmang C; Standards Task Force, et al.: Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum 46 (8): 1001-12, 2003. [PUBMED Abstract]
  55. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2019. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed October 15, 2019.
  56. Syngal S, Brand RE, Church JM, et al.: ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 110 (2): 223-62; quiz 263, 2015. [PUBMED Abstract]
  57. Glanz K, Grove J, Le Marchand L, et al.: Underreporting of family history of colon cancer: correlates and implications. Cancer Epidemiol Biomarkers Prev 8 (7): 635-9, 1999. [PUBMED Abstract]
  58. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61 (5): 759-67, 1990. [PUBMED Abstract]
  59. Vogelstein B, Kinzler KW: The multistep nature of cancer. Trends Genet 9 (4): 138-41, 1993. [PUBMED Abstract]
  60. Lengauer C, Kinzler KW, Vogelstein B: Genetic instabilities in human cancers. Nature 396 (6712): 643-9, 1998. [PUBMED Abstract]
  61. Kinzler KW, Vogelstein B: Colorectal tumors. In: Vogelstein B, Kinzler KW, eds.: The Genetic Basis of Human Cancer. 2nd ed. New York, NY: McGraw-Hill, 2002, pp 583-612.
  62. Thibodeau SN, Bren G, Schaid D: Microsatellite instability in cancer of the proximal colon. Science 260 (5109): 816-9, 1993. [PUBMED Abstract]
  63. Ionov Y, Peinado MA, Malkhosyan S, et al.: Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363 (6429): 558-61, 1993. [PUBMED Abstract]
  64. Peltomäki P, Lothe RA, Aaltonen LA, et al.: Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 53 (24): 5853-5, 1993. [PUBMED Abstract]
  65. Jass JR, Cottier DS, Pokos V, et al.: Mixed epithelial polyps in association with hereditary non-polyposis colorectal cancer providing an alternative pathway of cancer histogenesis. Pathology 29 (1): 28-33, 1997. [PUBMED Abstract]
  66. Jass JR: Serrated route to colorectal cancer: back street or super highway? J Pathol 193 (3): 283-5, 2001. [PUBMED Abstract]
  67. Wynter CV, Walsh MD, Higuchi T, et al.: Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer. Gut 53 (4): 573-80, 2004. [PUBMED Abstract]
  68. Bengoechea O, Martínez-Peñuela JM, Larrínaga B, et al.: Hyperplastic polyposis of the colorectum and adenocarcinoma in a 24-year-old man. Am J Surg Pathol 11 (4): 323-7, 1987. [PUBMED Abstract]
  69. Hyman NH, Anderson P, Blasyk H: Hyperplastic polyposis and the risk of colorectal cancer. Dis Colon Rectum 47 (12): 2101-4, 2004. [PUBMED Abstract]
  70. Leggett BA, Devereaux B, Biden K, et al.: Hyperplastic polyposis: association with colorectal cancer. Am J Surg Pathol 25 (2): 177-84, 2001. [PUBMED Abstract]
  71. McCann BG: A case of metaplastic polyposis of the colon associated with focal adenomatous change and metachronous adenocarcinomas. Histopathology 13 (6): 700-2, 1988. [PUBMED Abstract]
  72. Place RJ, Simmang CL: Hyperplastic-adenomatous polyposis syndrome. J Am Coll Surg 188 (5): 503-7, 1999. [PUBMED Abstract]
  73. Koide N, Saito Y, Fujii T, et al.: A case of hyperplastic polyposis of the colon with adenocarcinomas in hyperplastic polyps after long-term follow-up. Endoscopy 34 (6): 499-502, 2002. [PUBMED Abstract]
  74. Torlakovic E, Snover DC: Serrated adenomatous polyposis in humans. Gastroenterology 110 (3): 748-55, 1996. [PUBMED Abstract]
  75. Torlakovic EE, Gomez JD, Driman DK, et al.: Sessile serrated adenoma (SSA) vs. traditional serrated adenoma (TSA). Am J Surg Pathol 32 (1): 21-9, 2008. [PUBMED Abstract]
  76. Snover DC, Jass JR, Fenoglio-Preiser C, et al.: Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol 124 (3): 380-91, 2005. [PUBMED Abstract]
  77. Lash RH, Genta RM, Schuler CM: Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients. J Clin Pathol 63 (8): 681-6, 2010. [PUBMED Abstract]
  78. Torlakovic E, Skovlund E, Snover DC, et al.: Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 27 (1): 65-81, 2003. [PUBMED Abstract]
  79. Jass JR, Baker K, Zlobec I, et al.: Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a 'fusion' pathway to colorectal cancer. Histopathology 49 (2): 121-31, 2006. [PUBMED Abstract]
  80. Goldstein NS: Small colonic microsatellite unstable adenocarcinomas and high-grade epithelial dysplasias in sessile serrated adenoma polypectomy specimens: a study of eight cases. Am J Clin Pathol 125 (1): 132-45, 2006. [PUBMED Abstract]
  81. Lu FI, van Niekerk de W, Owen D, et al.: Longitudinal outcome study of sessile serrated adenomas of the colorectum: an increased risk for subsequent right-sided colorectal carcinoma. Am J Surg Pathol 34 (7): 927-34, 2010. [PUBMED Abstract]
  82. Schreiner MA, Weiss DG, Lieberman DA: Proximal and large hyperplastic and nondysplastic serrated polyps detected by colonoscopy are associated with neoplasia. Gastroenterology 139 (5): 1497-502, 2010. [PUBMED Abstract]
  83. Toyota M, Ahuja N, Ohe-Toyota M, et al.: CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96 (15): 8681-6, 1999. [PUBMED Abstract]
  84. Ahuja N, Mohan AL, Li Q, et al.: Association between CpG island methylation and microsatellite instability in colorectal cancer. Cancer Res 57 (16): 3370-4, 1997. [PUBMED Abstract]
  85. Samowitz WS, Albertsen H, Herrick J, et al.: Evaluation of a large, population-based sample supports a CpG island methylator phenotype in colon cancer. Gastroenterology 129 (3): 837-45, 2005. [PUBMED Abstract]
  86. Yamashita K, Dai T, Dai Y, et al.: Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell 4 (2): 121-31, 2003. [PUBMED Abstract]
  87. Weisenberger DJ, Siegmund KD, Campan M, et al.: CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet 38 (7): 787-93, 2006. [PUBMED Abstract]
  88. Chan AO, Issa JP, Morris JS, et al.: Concordant CpG island methylation in hyperplastic polyposis. Am J Pathol 160 (2): 529-36, 2002. [PUBMED Abstract]
  89. Kambara T, Simms LA, Whitehall VL, et al.: BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53 (8): 1137-44, 2004. [PUBMED Abstract]
  90. O'Brien MJ, Yang S, Clebanoff JL, et al.: Hyperplastic (serrated) polyps of the colorectum: relationship of CpG island methylator phenotype and K-ras mutation to location and histologic subtype. Am J Surg Pathol 28 (4): 423-34, 2004. [PUBMED Abstract]
  91. Yang S, Farraye FA, Mack C, et al.: BRAF and KRAS Mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol 28 (11): 1452-9, 2004. [PUBMED Abstract]
  92. Chan TL, Zhao W, Leung SY, et al.: BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 63 (16): 4878-81, 2003. [PUBMED Abstract]
  93. Rajagopalan H, Bardelli A, Lengauer C, et al.: Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418 (6901): 934, 2002. [PUBMED Abstract]
  94. Yuen ST, Davies H, Chan TL, et al.: Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 62 (22): 6451-5, 2002. [PUBMED Abstract]
  95. Deng G, Bell I, Crawley S, et al.: BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1, but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10 (1 Pt 1): 191-5, 2004. [PUBMED Abstract]
  96. McGivern A, Wynter CV, Whitehall VL, et al.: Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Fam Cancer 3 (2): 101-7, 2004. [PUBMED Abstract]
  97. Wang L, Cunningham JM, Winters JL, et al.: BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res 63 (17): 5209-12, 2003. [PUBMED Abstract]
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