Genetic characterisation of patients with multiple colonic polyps.

Two main hereditary colorectal cancer syndromes have been described, namely familial adenomatous polyposis coli (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). FAP is a disease characterised by autosomal dominant inheritance where the affected subjects develop hundreds to thousands of adenomatous polyps throughout the whole colon, usually during their teenage years. This syndrome is also characterised by the development of a variable range of extracolonic manifestations. 2 Germline mutations in the APC gene are responsible for FAP. Almost all mutations are nonsense or frameshift and result in the premature truncation of the protein. Patients with 5′ or 3′ mutations in the APC gene tend to present with fewer adenomas (0-100) and are described as having attenuated FAP (AAPC). 7 HNPCC is also characterised by dominant inheritance and by the development of colorectal as well as various extracolonic cancers. Some studies have now shown that colorectal cancers (CRCs) in HNPCC patients also derive from precursor lesions, although the progression from adenoma to carcinoma is probably a much faster process compared to the sporadic and FAP model. 9 HNPCC is caused by germline mutations in mismatch repair (MMR) genes, MSH2, MLH1, PMS1, PMS2, and MSH6. Accordingly, tumours originated through inactivation of the MMR pathway accumulate somatic mutations throughout the genome and especially in simple repeated sequences called microsatellites. Microsatellite instability (MSI) is the hallmark of most colorectal cancers (CRC) associated with HNPCC. As previously reported, there are a substantial number of patients presenting with an excess of colorectal tumours, both adenomas and carcinomas, although they do not fulfil the diagnostic criteria for either FAP or HNPCC. These subjects usually present with fewer than 100 polyps, sometimes associated with synchronous or metachronic carcinomas, without accompanying extracolonic features and often with a poorly described family history, if any. The genetic basis for these syndromes is still poorly understood and inconsistent findings have been reported. Pedemonte et al found that 5/18 patients with synchronous colorectal adenomas carried novel germline APC variants, whereas Beck et al found one germline missense mutation in the MLH1 gene (I219V) of uncertain functional effect in a cohort of 25 patients with similar clinical manifestations. Frayling et al found that two missense substitutions in the APC gene, I1307K and E1317Q, were associated with the presence of multiple colorectal adenomas or carcinomas in a minority of a larger cohort. More recently, Tomlinson et al have provided evidence based on linkage analysis for a new colorectal cancer gene, CRAC1, mapping to chromosome 15q14-q22 in an Ashkenazi family with a dominantly inherited predisposition to colorectal adenomas and carcinomas. However, a systematic analysis of the suppressor and mutator pathways in this type of patient has not been carried out yet. The aim of the present study was to evaluate in a group of patients with a marked excess of colorectal adenomas, often associated with carcinomas, whether a genetic defect could be detected in one of the two major pathways responsible for colorectal tumorigenesis, namely the WNT transduction pathway and DNA mismatch repair. We have analysed microsatellite instability as well as immunoexpression of MMR proteins (MSH2, MLH1, and MSH6) and of β-catenin. Germline mutations in APC or in the MMR genes have been investigated in those cases where the MSI and/or IHC analyses were suggestive of a defect in either WNT signal transduction or mismatch repair pathways.