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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Major Genetic Syndromes

Table 8. Clinical Practice Guidelines for Diagnosis and Colon Surveillance of Familial Adenomatous Polyposis (FAP) continued...

Aberrant methylation of MLH1 is responsible for causing approximately 90% of sporadic MSI colon cancers.[262] Other mechanisms such as somatic MLH1 mutations may be responsible for the minority of cases where aberrant MLH1 methylation is absent.[262] In most studies, aberrant MLH1 methylation has been detected in only a small percentage of LS colon cancers in individuals with germline mutations in MLH1.[262,263,264,265] Thus, detection of aberrantly methylated MLH1 in colon cancer is more suggestive of a sporadic MSI tumor. Since assays of methylation are complex and resource-intensive, surrogate markers of MLH1 methylation have been examined. One study found that loss of immunohistochemical staining for p16 correlated strongly with both MLH1 methylation and BRAF V600E mutations (BRAF mutations are discussed in detail in the following paragraphs). However, only 30% of sporadic tumors examined in this study exhibited loss of p16 expression, limiting the utility of this assay.[266]

BRAF mutations have been detected predominantly in sporadic MSI tumors.[267,268,269,270] This suggests that somatic BRAF V600E mutations may be useful in excluding individuals from germline mutation testing. MLH1 hypermethylation and/or BRAF mutation testing are increasingly utilized in universal LS testing algorithms in an attempt to distinguish between an absence of MLH1 protein expression caued by hypermethylation and germline MLH1 mutations.

(Refer to the Diagnostic strategies for all individuals diagnosed with CRC (universal testing) section of this summary for more information about the clinical role of BRAF and hypermethylation testing.)


Reports of patients with germline MLH1 hypermethylation should not be confused with EPCAM mutation-induced hypermethylation of MSH2, as described below. Prior paragraphs have emphasized the issues associated with the common, acquired somatic hypermethylation of the MLH1 promoter. However, examples of hypermethylation of the MLH1 promoter described in the germline have generally not been associated with a stable Mendelian inheritance.

A comprehensive review of MLH1 constitutional epigenetic alterations involving hypermethylation of one MLH1 allele has been published.[271] Such epimutations are seen in patients with early-onset LS and/or multiple tumors of the LS type. Germline sequence variations or rearrangements are not seen in these patients, although the tumors show MSI-H, loss of MLH1 protein expression, and an absence of BRAF V600E mutations. These patients commonly have no family history of LS-like tumors. Interestingly, inheritance appears to be maternal, and therefore non-Mendelian. The constitutional monoallelic hypermethylation may appear as a mosaic, involving different tissues to a varying extent. In addition, the constitutional epimutation is typically reversible in the course of meiosis, such that offspring are usually unaffected. Because inheritance has been demonstrated in very few families, performing genetic counseling and genetic testing (which requires specialized research techniques) is particularly challenging.


Tumors with MSI and loss of MSH2 protein expression are generally indicative of an underlying MSH2 germline mutation (inferred MSH2 mutation). Unlike the case with MLH1, MSI with MSH2 loss is rarely associated with somatic hypermethylation of the promoter. Nevertheless, in at least 30% to 40% of these cases of inferred MSH2 mutation, no germline mutation can be detected with state of the art technology. One Chinese family with tumors showing MSH2 loss was found to have allele-specific hypermethylation that appeared to have been an inherited phenomenon.[272] Another study of a family with MSH2-deficient MSI-high tumors employed the commonly used diagnostic MLPA analysis of MSH6 and also showed reduced expression of MSH6. In doing so, a decrease in signal was observed for exon 9 of the EPCAM (TACSTD1) gene, which is near MSH2. Use of additional MLPA probes located between exon 3 of EPCAM and exon 1 of MSH2 demonstrated that the deletion spanned most 3' exons of EPCAM, but spared the MSH2 promoter.[273] The mutation in EPCAM was found to induce the observed methylation of the MSH2 promoter by transcription across a CpG island within the promoter region. The presence of EPCAM mutations showing similar methylation-mediated MSH2 loss was found at about the same time in families from Hungary.[274]. On the strength of these observations, EPCAM testing has already been introduced clinically for patients with loss of MSH2 protein expression in their CRCs who lack detectable MSH2 germline mutation. One study of two families with the same EPCAM deletion found few extracolonic cancers and no endometrial cancers.[275]


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Last Updated: February 25, 2014
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