Role of bax Mutations in Apoptosis in Colorectal Cancers With Microsatellite Instability

Half of colorectal tumors with microsatellite instability contain frameshift mutations in the (G)8 tract of bax, a major apoptosis effector, but their functional significance remains unclear. We studied the role of bax mutations on bax expression and apoptosis in 59 primary colorectal cancers of which 41 were microsatellite unstable. Tumors were screened for bax(G)8 mutations and evaluated immunohistochemically for bax, bcl-2, and p53 protein expression and apoptotic (M30 cytoDEATH) and proliferative (Ki-67) indexes. We identified bax(G)8 mutations in 20 (49%) of 41 unstable tumors; the mutations were associated significantly with proximal, poorly differentiated, or mucinous adenocarcinomas. Most bax-mutated cases displayed a bax-immunonegative zone in all or part of the tumor that was proved to correspond to biallelic bax(G)8 mutations by microdissection and to confer growth advantage to the tumor by decreasing apoptosis compared with adjacent bax-immunopositive tumor. Biallelic bax(G)8 mutations are subject to positive selection pressure and might disable apoptosis in colorectal cancer. There is substantial evidence that apoptosis has a role in the development of human cancer and that it might be a major mechanism in the action of current anticancer drugs. 1 Members of the bcl-2 family of proteins that regulate apoptotic signaling through mitochondria are key players in the determination of cell survival and death. 2,3