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...
Because many colon cancers demonstrate frameshift mutations at a small percentage of microsatellite repeats, the designation of an adenocarcinoma showing MSI depends, in part, on the detection of a specified percentage of unstable loci from a panel of dinucleotide and mononucleotide repeats that were selected at a National Institutes of Health Consensus conference. If more than 30% of a tumor's markers are unstable, it is scored as MSI-H; if at least one, but fewer than 30% of markers are unstable, the tumor is designated MSI-low (MSI-L). If no loci are unstable, the tumor is designated MSS. Most tumors arising in the setting of LS will be MSI-H. The clinical relevance of MSI-L tumors remains controversial at this point. The probability of finding a germline mutation in a MMR gene in this setting is very small. One distinction is that people with germline mutations in MSH6 do not necessarily manifest the MSI-H phenotype. One study presented evidence that MSH6 mutations were associated with cancers having an MSI-L phenotype. However, a second study found that 18/21 (86%) of CRCs in MSH6 carriers showed MSI-H. In addition, in sporadic cancers with MSI-L phenotype, MSH6 mutations were not found.
(Refer to the Diagnostic strategies for all individuals diagnosed with CRC (universal testing) section of this summary for information about the utilization of MSI status in the diagnostic work-up of a patient with suspected LS.)
(Refer to the Issues With Informed Consent for MSI and IHC Tumor Testing section in the Psychosocial Issues in Hereditary Colon Cancer Syndromes section of this summary for information about educational strategies and issues related to informed consent for MSI and IHC testing.)
The complexity of aberrant methylation of MMR genes
AberrantMLH1methylation in sporadic CRC
The presence of an MSI-H tumor associated with loss of MSH2, MSH6, or PMS2 protein expression strongly supports a diagnosis of LS. However, MSI-H tumors with absent MLH1 protein expression present a more complex scenario. MSI occurs in approximately 10% to 15% of sporadic CRC (generally, patients aged >50 years and with little or no family history). In sporadic CRC, absent MLH1 protein expression is a consequence of aberrant MLH1 methylation, a somatic event confined to the tumor that in the vast majority of cases is not heritable. Since loss of MLH1 protein expression occurs in both LS and sporadic tumors, its specificity for predicting germline MMR gene mutations is lower than for the other MMR proteins.
Because of this uncertainty, additional molecular testing is often necessary to clarify the etiology of MLH1 absence in these cases. Other somatic changes in colon cancers that appear to have negative predictive value for identifying individuals with germline mutations in one of the MMR genes are BRAF mutations and MLH1 promoter methylation.