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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...

Practices and pitfalls in testing

One study reported that of 42 population-based probands harboring deleterious MSH6 germline mutations who were ascertained independent of their family cancer history, 30 (71%) had a family cancer history that did not meet the Amsterdam II criteria.[218]

MSH6 colorectal tumors can be MSI-H, MSI-L, or MSS. This pitfall illustrates the utility of IHC for the MMR protein expression. Eighteen of 21 (86%) of the colorectal tumors showed an MSI-H phenotype. Of the 16 endometrial tumors tested, 11 were MSI-H (69%); four were MSI-L (25%), and one was MSS (6%).[265]

In endometrial cancers with germline MSH2 mutations, loss of MSH6 frequently occurs with loss of MSH2.[319,325]



The prevalence of PMS2 germline mutations has been underappreciated for many reasons. It is the most recent of the major genes to be identified, probably has the lowest prevalence, was not felt to be worthy of serious investigation, and commercial testing is not widely available.[326,327,328] One registry study reported an incidence of 2.2% for PMS2 mutations in 184 patients with suspected LS.[329] A population-based study reported a prevalence of approximately 5% (1 of 18).[212]

Genotype-phenotype correlations

A meta-analysis of three population-based studies and one clinic-based study estimated that for carriers of PMS2 mutations, the risk of CRC to age 70 years was 20% among men and 15% among women, and the risk of endometrial cancer was 15%.[216]

In one study, patients with PMS2 mutations presented with CRC 7 to 8 years later than did those with MLH1 and MSH2 mutations. However, these families were small and did not fulfill Amsterdam criteria.[329]

Polymorphisms in Unrelated Genes Affecting Expression in LS

Polymorphisms potentially affecting expression in MMR genes fall into two categories: those whose mechanisms are already suspected to have an effect on cancer-related pathways, and those that are truly anonymous. Several candidate genes have been studied. Anonymous genes have also been evaluated.

Studies have demonstrated that a polymorphism in the promoter region of the insulin-like growth factor 1 (IGF1) gene modifies age of onset of CRC in LS.[330,331]. The polymorphism is a variable number of CA-dinucleotide repeats approximately 1 kb upstream of the transcription start site of IGF1. There is significant variability between individuals and populations with respect to repeat length. Carriers of shorter repeat lengths (shortest allele ≤17 repeats) develop CRC on average 12 years earlier than those with longer repeat lengths. It is unclear whether this polymorphism influences extracolonic malignancies. Additionally, the cyclin D1 polymorphism G870A may be associated with earlier age of onset of CRC in LS,[332,333] although the association appears to be more reproducible in MSH2 mutation carriers than in MLH1 mutation carriers.[333,334]

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