A missense mutation in both hMSH2 andAPC in an Ashkenazi Jewish HNPCC kindred: implications for clinical screening

Editor—Colorectal carcinoma (CRC), among the most common neoplasms in humans, has a moderately large hereditary component. The two most frequent hereditary CRC syndromes are hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), both dominantly inherited disorders. HNPCC is caused by inherited defects in the DNA mismatch repair (MMR) genes hMLH1 , hMSH2 , PMS1 , and PMS2 ; FAP is caused by mutations in the APC gene.1 Between 1 and 4% of all CRC fully satisfy the international criteria for HNPCC.2-4 In addition to CRC, these families also have an excess incidence of adenocarcinoma of the endometrium and to a lesser degree, cancer of the stomach, ovary, and other sites.5 Alterations in hMSH2 or hMLH1 account for ∼90% of the germline mutations detected in HNPCC.1 Mutations in hMSH6 have been described in CRC kindreds that resemble HNPCC but do not always fulfil the above mentioned criteria.6 ,7 Familial adenomatous polyposis (FAP) accounts for less than 1% of CRC; it is characterised by the development of a large number (>100) of colorectal polyps, which, if untreated, will inevitably lead to CRC.8 The gene underlying FAP, APC, was identified in 1991; germline mutations truncating the APC gene product are usually found in FAP.9 ,10 An interesting missense variant in APC , I1307K, was discovered in a 39 year old man with eight colorectal polyps11 with a family history of colorectal polyps and CRC but not FAP. The T to A polymorphism at nt 3920 in APC was postulated to predispose to cancer, not as a direct effect of the protein, but by rendering its region of APC hypermutable. The mutation does not seem to be common in populations other than Ashkenazi Jews, where it is found at a …