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Updated: Aug 24, 2026
Multi-Gene Single Nucleotide Polymorphism Detection in Gastric Cancer Based on Ion Semiconductor Sequencing Platform
Published on: May 10, 2024
Inactivating mutation of the pro-apoptotic gene BID in gastric cancer
Jong Heun Lee1, Young Hwa Soung, Jong Woo Lee
1Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea. stingray@catholic.ac.kr
Abstract:
There is evidence that deregulation of apoptosis is mechanistically involved in cancer development and somatic mutations of apoptosis-related genes have been reported in human cancers. BID, a pro-apoptotic member of the Bcl-2 family, interconnects the extrinsic apoptosis pathway initiated by death receptors to the intrinsic apoptosis pathway. To explore the possibility that genetic alterations of BID might be involved in the development of human cancers, this study analysed the entire coding region and all splice sites in the human BID gene in 67 advanced gastric carcinomas. Overall, four BID mutations (6.0%) were detected that consisted of one frameshift and three missense mutations. The tumour-derived BID mutants were expressed in 293T cells and it was found that, compared with wild-type BID, the frequency of apoptosis was significantly reduced in cells expressing the gene containing the frameshift mutation. Furthermore, expression of the inactivating frameshift mutant interfered with cell death by overexpression of death receptors, indicating that this mutant inhibits the extrinsic apoptosis pathway in a dominant-negative fashion. Also, the frameshift mutation rendered cancer cells resistant to apoptosis induced by the anti-cancer drug 5-fluorouracil (5-FU). This is the first report of BID gene mutation in human malignancy. The data suggest that such mutations occur rarely in gastric cancers and that only a small fraction of BID mutations may lead to the loss of its apoptotic function.
Insights
Genetic alterations in the BID gene, crucial for apoptosis, were investigated in gastric cancer. A frameshift mutation was found to inhibit apoptosis and confer resistance to 5-FU, suggesting a rare role in cancer development.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Cell Death Research
Background:
- Deregulation of apoptosis is a hallmark of cancer.
- The BID gene, a pro-apoptotic member of the Bcl-2 family, bridges extrinsic and intrinsic apoptosis pathways.
- Somatic mutations in apoptosis-related genes are implicated in human cancers.
Purpose of the Study:
- To investigate the potential involvement of genetic alterations in the human BID gene in the development of advanced gastric carcinomas.
- To analyze the functional consequences of detected BID mutations on apoptosis regulation.
Main Methods:
- Sequencing of the entire coding region and splice sites of the human BID gene in 67 advanced gastric carcinoma samples.
- Expression of wild-type and mutant BID in 293T cells to assess apoptosis frequency.
- Evaluation of the dominant-negative effect of the frameshift mutant on death receptor-mediated apoptosis.
- Assessment of apoptosis resistance to 5-fluorouracil (5-FU) in cancer cells expressing the BID frameshift mutant.
Main Results:
- Four BID mutations (6.0%), including one frameshift and three missense mutations, were detected in advanced gastric carcinomas.
- The frameshift BID mutant significantly reduced apoptosis frequency compared to wild-type BID.
- The frameshift mutant exhibited dominant-negative inhibition of the extrinsic apoptosis pathway and conferred resistance to 5-FU-induced apoptosis.
Conclusions:
- This study reports the first instance of BID gene mutation in human malignancy.
- BID gene mutations appear to be rare in gastric cancers.
- The identified frameshift mutation can inactivate BID's apoptotic function, potentially contributing to cancer development and drug resistance.
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