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Approximately 15% of sporadic large bowel cancers show DNA replication errors (RERs) or DNA microsatellite instability. 1 2 Strand et al 3 reported that mutations of DNA mismatch repair genes produced destabilisation of tracts of simple repetitive DNA in yeast and linked this observation to similar findings in both sporadic colorectal cancer and hereditary non-polyposis colorectal cancer (HNPCC). 4 This led to the cloning of human DNA mismatch repair genes, of which hMSH2 and hMLH1 were shown to be implicated in most cases of HNPCC. 5-8
Although sporadic RER positive colorectal cancers are viewed as non-familial counterparts of HNPCC, only a subset of sporadic RER positive cancers shows somatic mutation of hMSH2, hMLH1, or other DNA mismatch repair genes such as hPMS1 and hPMS2. 9 10 This suggests that a proportion of RER positive CRC is not necessarily an exact sporadic counterpart of HNPCC. Either different DNA mismatch repair genes are implicated or the genes are switched off by altered methylation or the DNA microsatellite instability may be mild and epiphenomenal. For example, mild DNA microsatellite instability (one locus only) was not associated with certain features characterising HNPCC including poor tumour differentiation, location in proximal colon, and diploid DNA content. 11 Conversely these features were seen when two or more loci were implicated. 11 Further features of strongly RER positive sporadic cancers have been recognised including mucinous differentiation, 12 a Crohn's like peritumoural lymphocytic reaction, 13 14 and tumour multiplicity. 15 16
RER positive cancers, whether sporadic or associated with HNPCC, appear to show a molecular genetic spectrum that is distinct from common bowel cancer or cancer developing in familial adenomatous polyposis. APC, p53, and K-ras mutations occur with reduced frequency in HNPCC. 17 In sporadic RER positive cancers there is a reduced frequency of p53 immunostaining 13 14 whereas mutations within small repeated sequences are found in three genes implicated in tumour progression: TGFβRII, 18 IGFIIR, 19 and BAX. 20 Mutations in TGFβRII are also found in adenomas and carcinomas from patients with HNPCC. 17 21
The preceding data indicate that sporadic RER positive cancers differ in clinical, pathological, and molecular respects from sporadic RER negative cancers, but at least partly overlap with HNPCC. Conflicting data are explained by less stringent definitions of...