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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...

In the absence of additional family or personal history suggestive of LS, isolated cases of CRC diagnosed prior to age 36 years are uncommonly associated with MMR gene mutations. One study found MMR mutations in only 6.5% of such individuals.[257] Therefore, isolated cases of very early-onset CRC should be offered tumor screening with MSI/IHC rather than proceeding directly to germline mutation analysis.

MSI/IHC in adenomas

Current practice is to offer colonoscopy surveillance to those with strong family histories but no prior genetic or tumor testing. At times, adenomas are detected during these colonoscopies. In the instance 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 mutations found 8 of 12 adenomas to have both MSI and IHC protein loss.[258] However, the study authors emphasized that normal MSI/IHC testing in an adenoma does not exclude LS.


Microsatellites are short, repetitive sequences of DNA (often mononucleotides, dinucleotides, or trinucleotides) located throughout the genome, primarily in intronic sequences.[259,260] The term microsatellite instability (MSI) is used when tumor DNA shows alterations in microsatellite regions when compared with normal tissue. MSI indicates probable defects in MMR genes, which may be due to somatic or germline mutations or epigenetic alterations.[261] In most instances, MSI is associated with absence of protein expression of one or more of the MMR proteins (MSH2, MLH1, MSH6, and PMS2). However, loss of protein expression may not be seen in all MSI-H tumors.

Certain histopathologic features are strongly suggestive of MSI phenotype including the presence of tumor infiltrating lymphocytes, Crohn-like reaction, mucinous histology, absence of dirty necrosis, and histologic heterogeneity. These histologic features have been combined into computational scores that have high predictive value in identifying MSI CRCs.[262,263]

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.[264] 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.[264] The clinical relevance of MSI-L tumors remains controversial. 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.[248] However, a second study found that 18/21 (86%) of CRCs in MSH6 carriers showed MSI-H.[265] In addition, in sporadic cancers with MSI-L phenotype, MSH6 mutations were not found.[266]

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