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

Table 10. Clinical Practice Guidelines for Colon Surveillance of BiallelicMYH-Associated Polyposis (MAP) continued...

The term "familial colorectal cancer type X" or "FCCX" was coined to refer to families who meet Amsterdam criteria but lack MSI/IHC abnormalities.[217] Some refer to FCCX as "Lynch-like syndrome." Complicating the terminology further, the term "Lynch-like" has also been used in cases with MSI-H tumors and presumed underlying MMR germline mutation, but in which no such mutation is detected.

In LS,[218,219,220] unlike FAP, most patients do not have an unusual number of polyps. LS accounts for about 1% to 3% of all CRCs.[221] LS is an autosomal dominant syndrome characterized by an early age of onset of CRC, excess synchronous and metachronous colorectal neoplasms, right-sided predominance, and extracolonic tumors. LS is caused by mutations in the DNA MMR genes, namely MLH1, MSH2, MSH6, and PMS2. Mutations of the EPCAM gene that result in hypermethylation and silencing of MSH2 have also been described. (Refer to the MSI section in the Major Genetic Syndromes section of this summary for more information.) The average age of CRC diagnosis in LS mutation carriers is 44 to 52 years [221,222,223] and 71 years in sporadic CRC.[224] In mutation-positive families when probands were excluded and both affected and nonaffected relatives were ascertained, the average age at diagnosis of CRC was reported to be 61 years,[225] suggesting ascertainment bias in early reports.

The lifetime risk of CRC in MLH1 and MSH2 mutation carriers was 68.7% in males and 52% in females.[225] However, in a meta-analysis of three population-based studies and one clinic-based study, the lifetime risk of CRC in MLH1 and MSH2 mutation carriers was reported to be 53% in males and 33% in females.[226,227] In a study of 113 families with MSH6 mutation carriers, the estimated cumulative risk of CRC in males was 22% and 10% in females.[228]PMS2 lifetime CRC risk to age 70 years has been reported to be 20% in males and 15% in females.[229] A large registry-based study from France estimated CRC risk at age 70 years to be 41% for MLH1 mutation carriers, 48% for MSH2 mutation carriers, and 12% for MSH6 mutation carriers.[230]

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