Evaluation of the replication error phenotype in relation to molecular and clinicopathological features in hereditary and early onset colorectal cancer

Mutations affecting human mismatch repair (MMR) genes (MLH1, MSH2, PMS1, PMS2, and MSH6) cause tumour predisposition in hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, and an association has been demonstrated with the replication error (RER) phenotype in most colorectal and some extracolonic neoplasms. A pathogenetic model for RER + tumours through inactivation of suppressor genes has been hypothesised, and TGFβRII, BAX and IGFIIR genes have recently been proposed as targets of such inactivating mutations. In this study, a series of 47 tumours developed in patients with known MLH1/MSH2 status and a family history of HNPCC and/or early onset colorectal cancer were characterised for the RER phenotype through microsatellite analysis. The RER phenotype, displayed by 17 tumours, was then correlated with the presence of insertions/deletions at the TGFβRII, IGFIIR and BAX gene stretches, confirming that the TGFβRII inactivation may be particularly critical for the RER-associated tumorigenesis. RER+ colorectal cancers (CRCs) developed more frequently in patients from HNPCC families (72.7%) than in those from families not fulfilling the Amsterdam criteria (33.3% in suspected HNPCC and 20.8% in early onset CRC patients). A consistent fraction of either Amsterdam and non-Amsterdam patients developed RER- CRCs, pointing to the involvement of other genes not related to the MMR system. The RER phenotype was associated with younger age at diagnosis in familial cases, and there was a trend for an association with proximal CRC localisation and early Dukes' stages. The RER status was also correlated with the presence and type of MLH1 and MSH2 alteration.