Genetic susceptibility to non-polyposis colorectal cancer

Familial colorectal cancer (CRC) is a major public health problem by virtue of its relatively high frequency. Some 15-20% of all CRCs are familial. Am ong these, familial adenomatous polyposis (FAP), caused by germline mutatio ns in the APC gene, accounts for less than 1%. Hereditary non-polyposis col orectal cancer (HNPCC), also called Lynch syndrome, accounts for approximat ely 5-8% of all CRC patients. Among these, some 3% are mutation positive, t hat is, caused by germline mutations in the DNA mismatch repair genes that have so far been implicated (MLH1, MSH2, MSH6, PMS1, and PMS2). Most of the remaining patients belonging to HNPCC or HNPCC-like families are still mol ecularly unexplained. Among the remaining familial CRCs, a large proportion is probably caused by gene mutations and polymorphisms of low penetrance, of which the I1307K polymorphism in the APC gene is a prime example. Molecular genetic findings have enabled hereditary CRC to be divided into t wo groups: (1) tumours that show microsatellite instability (MSI), occur mo re frequently in the right colon, have diploid DNA, harbour characteristic mutations such as transforming growth factor beta type II receptor and BAX, and behave indolently, of which HNPCC is an example; and (2) tumours with chromosomal instability (CIN), which tend to be left sided, show aneuploid DNA, harbour characteristic mutations such as K-ras, APC, and p53, and beha ve aggressively, of which FAP is an example. This review focuses most heavily on the clinical features, pathology, molec ular genetics, surveillance, and management including prophylactic surgery in HNPCC. Because of the difficulty in diagnosing HNPCC, a detailed differe ntial diagnosis of the several hereditary CRC variants is provided. The ext ant genetic and phenotypic heterogeneity in CRC leads to the conclusion tha t it is no longer appropriate to discuss the genetics of CRC without defini ng the specific hereditary CRC syndrome of concern. Therefore, it is import ant to ascertain cancer of all anatomical sites, as well as non-cancer phen otypic stigmata (such as the perioral and mucosal pigmentations in Peutz-Je ghers syndrome), when taking a family cancer history.