Systematic identification of genes with coding microsatellites mutated in DNA mismatch repair-deficient cancer cells

Microsatellite instability (MSI) caused by deficient DNA mismatch-repair fu nctions is a hallmark of cancers associated with the hereditary nonpolyposi s colorectal cancer (HNPCC) syndrome but is also found in about 15% of all sporadic tumors. Most affected microsatellites reside in untranslated inter genic or intronic sequences. However, recently few genes with coding micros atellites were also shown to be mutational targets in MSI-positive cancers and might represent important mutation targets in their pathogenesis. The s ystematic identification of such genes and the analysis of their mutation f requency in MSI-positive cancers might thus reveal major clues to their fun ctional role in MSI-associated carcinogenesis. We therefore initiated a sys tematic database search in 33,595 distinctly annotated human genes and iden tified 17,654 potentially coding mononucleotide repeats (cMNRs) and 2,028 c oding dinucleotide repeats (cDNRs), which consist of n greater than or equa l to 6 and n greater than or equal to 4 repeat units, respectively. Express ion pattern and mutation frequency of 19 of these genes with the longest re peats were compared between DNA mismatch repair-deficient (MSI+) and profic ient (MSS) cancer cells. Instability frequencies in these coding microsatel lite genes ranged from 10% to 100% in MSI-H tumor cells, whereas MSS cancer cells did not show mutations. RT-PCR analysis further showed that most of the affected genes (10/15) were highly expressed in tumor cells, The approa ch outlined here identified a new set of genes frequently affected by mutat ions in MSI-positive tumor cells. It will lead to novel and highly specific diagnostic and therapeutic targets for microsatellite unstable cancers. (C ) 2001 Wiley-Liss, Inc.