SOMATIC FRAMESHIFT MUTATIONS IN THE BAX GENE IN COLON CANCERS OF THE MICROSATELLITE MUTATOR PHENOTYPE

Cancers of the microsatellite mutator phenotype (MMP) show exaggerated genomic instability at simple repeat sequences. More than 50 percent (21 out of 41) of human MMP(+) colon adenocarcinomas examined were fou nd to have frameshift mutations in a tract of eight deoxyguanosines [( G)(8)] within BAX, a gene that promotes apoptosis. These mutations wer e absent in MMP tumors and were significantly less frequent in (G), re peats from other genes. Frameshift mutations were present in both BAX alleles in some MMP(+) colon tumor cell lines and in primary tumors. T hese results suggest that inactivating BAX mutations are selected for during the progression of colorectal MMP(+) tumors and that the wild-t ype BAX gene plays a suppressor role in a p53-independent pathway for colorectal carcinogenesis.