Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution
Y Ionov1, H Yamamoto, S Krajewski
1The Burnham Institute, La Jolla Cancer Research Center, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Abstract:
A remarkable instability at simple repeated sequences characterizes gastrointestinal cancer of the microsatellite mutator phenotype (MMP). Mutations in the DNA mismatch repair gene family underlie the MMP, a landmark for hereditary nonpolyposis colorectal cancer. These tumors define a distinctive pathway for carcinogenesis because they display a particular spectrum of mutated 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) mononucleotide tract. However, the functional significance of these mutations in tumor 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 alleles frequently appeared after inoculation into nude mice of single-cell clones of colon tumor cell lines with normal alleles. In contrast, no clones of BAX-expressing cells were found after inoculation of homozygous cell clones without wild-type BAX. These results support the interpretation that BAX inactivation contributes to tumor progression by providing a survival advantage. In this context, survival analyses show that BAX mutations are indicators of poor prognosis for both colon and gastric cancer of the MMP.
Insights
Microsatellite mutator phenotype (MMP) gastrointestinal cancers show BAX gene mutations. Inactivating BAX provides a survival advantage, contributing to tumor progression and indicating a poor prognosis in these cancers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Gastrointestinal cancers with a microsatellite mutator phenotype (MMP) exhibit instability in DNA sequences.
- This phenotype is linked to mutations in DNA mismatch repair genes, a hallmark of hereditary nonpolyposis colorectal cancer.
- The BAX gene, a proapoptotic factor, is frequently mutated in MMP gastrointestinal cancers.
Purpose of the Study:
- To investigate the functional significance of BAX mutations in tumor progression within the context of MMP gastrointestinal cancers.
- To determine if BAX inactivation confers a selective advantage during the clonal evolution of tumors.
- To establish BAX mutations as prognostic indicators for MMP-associated colon and gastric cancers.
Main Methods:
- Analysis of BAX frameshift mutations in colon and gastric cancer cell lines with MMP.
- Inoculation of single-cell clones with varying BAX allele status (wild-type, mutant, homozygous mutant) into nude mice.
- Monitoring tumor subclone evolution and survival in vivo.
- Correlation of BAX mutation status with patient survival data.
Main Results:
- Tumor subclones lacking wild-type BAX alleles frequently emerged after inoculation of cells with normal BAX alleles.
- No BAX-expressing clones were detected after inoculation of cells lacking wild-type BAX.
- BAX inactivation was shown to provide a survival advantage to tumor cells.
- BAX mutations were identified as indicators of poor prognosis in colon and gastric cancers of the MMP.
Conclusions:
- BAX inactivation contributes to tumor progression in MMP gastrointestinal cancers by conferring a survival advantage.
- The loss of functional BAX is a critical event in the evolution of these tumors.
- BAX mutations serve as a significant prognostic marker for patients with MMP-associated colon and gastric cancers.
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