Germline mutation and genome instability

Colorectal tumorigenesis has been associated with the progressive acquisition of a variety of genomic alterations in neoplastic cells. In 5-10% of cases, a strong family history of cancer suggests a major predisposition, either familial adenomatous polyposis (FAP) or HNPCC syndrome. In 1987, the gene responsible for FAP was localized on chromosome 5q. In 1991, the International Collaborative Group on HNPCC set stringent criteria for the diagnosis of HNPCC, to homogenize families that should be entered in large linkage analyses. In the past five years, five MMR genes could be identified as the site of germline mutations associated with a HNPCC syndrome (MSH2, MLH1, PMS1, PMS2, and MSH6). The TGFbeta RII gene has been found mutated at the germline level in a small number of HNPCC patients. The DNA mismatch repair pathway is essential for the correct maintenance of genetic information. The slippage occurs usually at microsatellite loci and the defect of one MMR gene leads to the accumulation of replication errors in such deficient cells. The tumours that exhibit the highest frequency of RER at microsatellite loci, thus termed RER+, account for 10-15% of all colorectal cancers, and for 92% of those developed in a context of a HNPCC syndrome.