Frameshift mutations at coding mononucleotide repeats of the hRAD50 gene in gastrointestinal carcinomas with microsatellite instability

Microsatellite instability (MSI) and frameshift mutations in genes containi ng nucleotide repeats have been reported in a subset of colorectal and gast ric carcinomas. This study describes the analysis of MSI-positive colorecta l (39 cases) and gastric carcinomas (36 cases) for the presence of frameshi ft mutations of the six genes known to be involved in DNA repair and contai ning mononucleotide repeats in their coding region. Our mutational study of the 75 MSI-positive tumors revealed frequent mutations in hRAD50 (23 cases , 31%), BLM (16 cases, 21%), and hMSH6 (16 cases, 21%); rare mutations in B RCA1 (1 case, 1%) and ATM (3 cases, 4%); and no mutation in NBS1. In contra st, no frameshift mutation was found in 60 MSI-negative colorectal and gast ric carcinomas. The mutation of hRAD50, a gene that is involved in the resp onse to cellular DNA damage and forms a complex with hMRE11 and NBS1, has n ot been reported previously. Our results suggest that frameshift mutations of hRAD50, BLM, and hMSH6 are selected and play a role in the tumorigenesis of colorectal and gastric carcinomas with MSI. The MSI targeting of the hR AD50 and BLM genes represents an additional link between MSI and DNA repair because alteration of these genes could accelerate defective DNA repair.