Abstract
An exacerbated genomic instability characterizes hereditary and sporadic gastrointestinal cancer of the microsatellite mutator phenotype (MMP), generating somatic frameshift mutations in genes containing mononucleotide repeats. We have recently shown that approximately 50, 40, and 30% of MMP + colon tumors harbor frameshift mutations in (G)8, (A)8, and (C)8 tracks within the proapoptotic gene BAX and the hMSH3 and hMSH6 DNA mismatch repair genes, respectively. Here we report a higher incidence of frameshift mutations in these 3 genes in a panel of 25 MMP+ gastric adenocarcinomas: 64% in BAX and hMSH3, and 52% in hMSH6. These results support a multiple mutator gene model for the stepwise unfolding of the MMP and further illustrate the importance of the escape from apoptosis in gastrointestinal cancer. The tumor suppressor role played by BAX is also supported by the finding of other somatic BAX mutations, including recurrent missense mutations, not only in gastrointestinal cancer of the MMP but also in gastrointestinal cancer without the MMP.
Footnotes
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↵1 Supported by NIH Grants CA63585 and CA38579. H. Y. is supported by a Postdoctoral Fellowship for Research Abroad from the Japan Society for the Promotion of Science.
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↵2 To whom requests for reprints should be addressed, at The Burnham Institute, La Jolla Cancer Research Center, 10901 North Torrey Pines Road, La Jolla, CA 92037. Phone: (619) 646-3112; Fax: (619) 646-3190; E-mail: mperucho@ljcrf.edu.
- Received May 28, 1997.
- Accepted July 31, 1997.
- ©1997 American Association for Cancer Research.