Genetic progression in microsatellite instability high (MSI-H) colon cancers correlates with clinico-pathological parameters: A study of the TGF betaRII, BAX, HMSH3, HMSH6, IGFIIR and BLM genes

Colon carcinomas with microsatellite mutator phenotype exhibit specific gen etic and clinico-pathological features. This report describes the analysis of 63 "microsatellite instability high" (MSI-H) tumors for the presence of mutations in microsatellites located in the coding regions (CDRs) of 6 gene s: TCF beta RII, BAX, hMSH3, hMSH6, IGFIIR, and BLM. The following frequenc ies of mutations were detected: TGF beta RII (70%), BAX (54%), hMSH3 (36.5% ), IGFIIR (22%), hMSH6(17.5%), and BLM (16%). The overall picture revealed combinations of mutations suggestive of a progressive order of accumulation , with mutations of TGF beta RII and BAX first, followed by frameshifts in hMSH3, hMSH6 IGFIIR, and BLM. Correlations with 12 clinico-pathological par ameters revealed that tumors with frameshifts in 1 or 2 CDRs were significa ntly better differentiated than tumors with frameshifts in more than 2 CDRs . We also found that mutations in the hMSH3 gene were significantly associa ted with decreased wall invasiveness and aneuploidy, and frameshifts in the BLM gene were significantly associated with the mucinous histotype. A tren d toward an association between hMSH3 and IGFIIR with the medullary and con ventional adenocarcinoma histotypes, respectively, was seen. Our results st rengthen the concept that mutations in target genes have a role in the tumo rigenic process of MSI-H tumors, and indicate that frameshifts in microsate llites located in CDRs occur in a limited number of combinations that could determine distinct clinico-pathological traits. (C) 2000 Wiley-Liss, Inc.