Two types of sporadic multiple colorectal cancers with and without HNPCC-like genetic instability

BACKGROUND/AIMS: Sporadic multiple colorectal cancers (MCCs) potentially ha ve similar genetic alterations to hereditary nonpolyposis colorectal cancer s (HNPCCs), but genetically unstable MCCs other than HNPCCs are not well ch aracterized. We report the frequency of HNPCC-like sporadic multiple colon cancers and their characterization as for HNPCC-related gene mutations. METHODOLOGY: Microsatellite instability (MSI) at 12 microsatellite loci was examined by a polymerase chain reaction in 19 cases each of MCC and single colorectal cancer (SCC). The target sequences of MSI, transforming growth factor beta type II receptor (TGF beta RII) gene, and the HNPCC genes, hMSH 2 and hMLH1, were amplified and analyzed for mutations by sequencing. RESULTS: In 5 of 19 cases with MCC, MSI was observed at more than 4 microsa tellite loci, and the other cases including all SCCs showed no MSI or MSI() at a single locus. In 4 of the 5 severe MSI(+) cases, a 10-bp adenine tra ct at codons 125-128 of the TGF beta RII gene was mutated. In terms of the hMSH2 and hMLH1 genes, only silent mutations and non-critical amino acid su bstitutions were found. CONCLUSIONS: We found severe MSI in 26% of sporadic multiple colorectal can cers. Mutations of the TGF beta RII gene are closely associated with severe MSI(+) MCCs as observed in HNPCC, suggesting that these MCCs develop by th e similar carcinogenic process to HNPCC.