Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution

A remarkable instability at simple repeated sequences characterizes gastroi ntestinal cancer of the microsatellite mutator phenotype (MMP). Mutations i n the DNA mismatch repair gene family underlie the MMP, a landmark for here ditary nonpolyposis colorectal cancer. These tumors define a distinctive pa thway for carcinogenesis because they display a particular spectrum of muta ted cancer genes containing target repeats for mismatch repair deficiency. One such gene is BAX, a proapoptotic member of the Bcl-2 family of proteins , which plays a key role in programmed cell death. More than half of colon and gastric cancers of the MMP contain BAX frameshifts in a (G)(8) mononucl eotide tract. However, the functional significance of these mutations in tu mor progression has not been established. Here we show that inactivation of the wild-type BAX allele by de novo frameshift mutations confers a strong advantage during tumor clonal evolution. Tumor subclones with only mutant a lleles frequently appeared after inoculation into nude mice of single-cell clones of colon tumor cell lines with normal alleles. In contrast, no clone s of BAX-expressing cells were found after inoculation of homozygous cell c lones without wild-type BAX. These results support the interpretation that BAX inactivation contributes to tumor progression by providing a survival a dvantage. In this context, survival analyses show that BAX mutations are in dicators of poor prognosis for both colon and gastric cancer of the MMP.