ASSOCIATION BETWEEN CPG ISLAND METHYLATION AND MICROSATELLITE INSTABILITY IN COLORECTAL-CANCER

De novo methylation of promoter region CpG islands has been increasing ly associated with transcriptional inactivation of important genes in neoplasia, To study the potential mechanisms underlying aberrant methy lation in cancer, we have determined the methylation patterns of selec ted genes in colorectal cancers with and without microsatellite instab ility (MI), which results from defects in one of several base mismatch repair genes, A total of 47 colorectal cancers were analyzed, of whic h 15 were MI+ (32%), We now report that both the frequency and the ext ent of de novo methylation are strikingly increased in MI+ cancers, Hy permethylation of the p16 gene was found in 60% of MI+ cancers, compar ed to only 22% in MI- cancers (P = 0,02). Similarly, hypermethylation of the thrombospondin-1 (TSP-1) gene, an angiogenesis inhibitor, was i ncreased in MI+ cancers (27% versus 0%; P = 0.008), Extensive methylat ion of insulin-like growth factor II (IGF2) and hypermethylated in can cer-1 (HIC-1) genes was observed in 60 and 80% of MI+ cancers, respect ively, as contrasted with 6 and 38% of MI- cancers (P = 0.0002 and 0.0 1, respectively). Furthermore, 60% of the MI+ cancers displayed the hy permethylation events at two or more loci in a concordant manner compa red to only 9% of the MI- cancers (P < 0.001), These results demonstra te a strong link between promoter hypermethylation and genetic instabi lity due to deficient DNA repair.