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Evidence exists that deregulation of apoptosis is involved in the mechanisms of cancer development, and the somatic mutations of apoptosis-related genes have been reported in human cancers. Bcl-XL/Bcl-2-associated death promoter (Bad), a proapoptotic member of Bcl-2 family, plays an important role in the intrinsic apoptosis pathway. To explore the possibility that the genetic alterations ofBadmight be involved in the development of human cancers, we analyzed the entire coding region and all splice sites of humanBadgene in 47 colon adenocarcinomas. Overall, we detected two somatic missense mutations (4.3%) inBadgene. Interestingly, both of theBadmutations were detected in the gene sequences encoding the Bcl-2 homology3 domain of Bad, which has a crucial role in inducing cell death. Transfection study revealed that both of the tumor-derived Bad mutants had decreased apoptosis activities compared with the wild-type Bad, indicating that theBadmutations reduced the cell death function of Bad. Co-immunoprecipitation assay revealed that binding of one of the tumor-derived Bad mutants with Bcl-2 and Bcl-XLis reduced. This is the first report onBadgene mutation in human malignancies, and our data suggest thatBadgene is occasionally mutated in colon cancers and that somatic mutation ofBadmay contribute to the development of colon cancers.

Inactivating mutations of proapoptotic Bad gene in human colon cancers