Replication error in colorectal carcinoma: Association with loss of heterozygosity at mismatch repair loci and clinicopathological variables

Instability of microsatellite DNA or replication error (RER) is characteris tic of tumours caused by mismatch repair (MMR) deficiency. Germline mutatio ns in MMR genes are associated with Hereditary non-polyposis colorectal car cinoma (HNPCC) and somatic mutations in these genes are also found in a sub stantial fraction of colorectal cancers (CRC). In this study we concurrentl y screened colorectal tumours for the RER phenotype and loss of heterozygos ity (LOH) at MMR gene loci. The RER phenotype was evident in 47/197 (24%) t umours. RER was more commonly detected in young patients (<50 pars) and in tumours located in the proximal colon. RER was positively associated with L OH at the hMSH2/hMSH6 loci on chromosome 2p, where LOH was observed in 46% of the RER+ tumours. LOH at hMLH1 and hPMS1 loci was more frequent in the y ounger patients (<50 years). RER was not associated with clinicopathologica l parameters, such as Duke's stage and tumour differentiation (grade). The RER phenotype was associated with better overall survival, but there was a trend towards significance when multivariate analysis was used. This indica tes that loss of MMR genes generate a less aggressive phenotype, and raises the question about RER being a useful indicator of prognosis for CRC patie nts.