Role of BAX mutations in mismatch repair-deficient colorectal carcinogenesis

Abstract

BAX gene mutations occur in approximately 50% of RER+ colorectal cancers. To determine the role of these mutations in tumour progression we analysed multiple di erent tumour sites from RER+ colorectal cancers for BAX mutations. Sixty colorectal carcinomas were analysed for microsatellite instability at loci BAT-26, L-myc, TGFbRII, D13S160 and D2S123. Twelve out of 60 tumours (20%) were RER+. Forty-®ve di erent 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, TGFbRII 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 TGFbRII mutation. These data suggest that mutations in TGFbRII 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 ®rst time later in tumour progression.

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

“…In the MMP pathway for gastrointestinal cancer, inactivation of TGF␤RII occurs relatively early (45,46). In contrast, the tumor suppressor function of BAX appears to occur later in tumor progression, as shown by the lack of clonality of these mutations in some tumors (15)(16)(17)(18)(19)47). However, the mutations that occur in BAX at a late stage of tumorigenesis are independent prognostic indicators of poor survival.…”

UVRAGmutations associated with microsatellite unstable colon cancer do not affect autophagy

“…Repetitive units like microsatellites are especially prone to undergo replication slippage, involving transient, local dissociations of the daughter and parental DNA strands with subsequent re-annealing between misaligned repeat units. 23,24 Failure to repair such mistakes from replication slippage leads to insertion or deletion (indel) of one or several base pairs. The UVRAG gene contains such a mononucleotide repeat of 10 adenines, (A)10, in the very beginning of exon 8, which encodes the coiled-coil domain responsible for interaction with Beclin 1 (Fig.…”

Death pathway genes Fas (Apo-1/CD95) and Bik (Nbk) show no mutations in colorectal carcinomas

“…12 Our results contrast with the high incidence of mutation in RER+ colorectal cancers in other genes, notably TGFb-RII (75%), 3 and Bax (50%). 4,5 This failure to identify any instance of clonal expansion of cells bearing Fas or Bik mutations thus suggests that such mutations confer no substantial growth advantage in colorectal carcinogenesis.…”