Role of BAX mutations in mismatch repair-deficient colorectal carcinogenesis

BAX gene mutations occur in approximately 50% of RER+ colorectal cancers. To determine the role of these mutations in tumour progression we analysed multiple different tumour sites from RER+ colorectal cancers for BAX mutations. Sixty colorectal carcinomas were analysed for microsatellite instability at loci BAT-26, L-myc, TGF betaRII, D13S160 and D2S123. Twelve out of 60 tumours (20%) were RER+. Forty-five different tumour sites from the 12 RER+ carcinomas were analysed for BAX mutations at the [(G)8] tract in exon 3. Six out of 12 (50%) RER+ tumours showed BAX mutations, four of which showed a homogenous pattern of such mutations detected in all tumour sites. In the other two cases, BAX mutations were present in some but not all tumour sites sampled from the same patient. In contrast, TGF betaRII mutations were found in 9/12 cases (75%) and in each of these were present in all the sampled sites. Two cases showed neither BAX nor TGF betaRII mutation. These data suggest that mutations in TGF betaRII may occur at a very early stage in tumour progression, perhaps in the founder clone. BAX mutations, however, are clearly not necessary for formation of the founder clone and can occur for the first time later in tumour progression.