Frameshift mutations at mononucleotide repeats in caspase-5 and other target genes in endometrial and gastrointestinal cancer of the microsatellite mutator phenotype

The majority of tumors from hereditary nonpolyposis colorectal cancer famil ies and a subset of unselected gastrointestinal and endometrial tumors exhi bit; a microsatellite mutator phenotype (MMP) that leads to the accumulatio n of hundreds of thousands of clonal mutations in simple repeat sequences. The mutated genes with positive or negative roles in cell growth or surviva l in aneuploid gastrointestinal cancer (e,g,, APC, K-ras, and p53) are less frequently mutated in near-diploid MR IP gastrointestinal tumors. These tu mors accumulate mutations in other genes, such as DNA mismatch repair hMSH3 and hMSH6 transforming growth factor-p type II receptor, and BAX,. All the se genes carry within their coding sequences, mononucleotide repeats that a re preferred targets for the MMP. Endometrial carcinoma is the most common type of extracolonic neoplasia in the hereditary nonpolyposis colorectal ca ncer syndrome, but the spectrum of its target cancer genes is not well char acterized. Here, we report that endometrial cancer of the MMP also accumula tes mutations in genes that are typically mutated in gastrointestinal cance r of the mutator pathway, including BAX (55%), hMSH3 (28%), and hMSH6 (17%) . We also report the detection of frameshift mutations in caspase-5, a memb er of the caspase family of proteases that has an (A)(10) repeal within its coding region, in MMP tumors of the endometrium, colon, and stomach (28, 6 2, and 44%, respectively), We therefore suggest caspase-5 as a new target g ene in the microsatellite mutator pathway for cancer.