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Published on: March 5, 2018
Inactivating mutations of caspase-8 gene in colorectal carcinomas
Hong Sug Kim1, Jong Woo Lee, Young Hwa Soung
1Department of Pathaology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Background & Aims:
There has been evidence that dysregulation of apoptosis is involved in the pathogenesis of cancer development. Caspase-8 is an initiation caspase that activates the caspase cascade during apoptosis. The aim of this study was to explore the possibility that mutation of the caspase-8 gene might be involved in the development of colorectal cancer.
Methods:
We analyzed the entire coding region of the caspase-8 gene for the detection of somatic mutations in 180 colorectal tumors (98 invasive carcinomas and 82 adenomas) by polymerase chain reaction, single-strand conformation polymorphism, and DNA sequencing.
Results:
Overall, we detected a total of 5 somatic mutations in 98 invasive carcinomas (5.1%), but no mutations were detected in 82 adenomas (0%). The frequency of caspase-8 mutation in the carcinomas was significantly higher than that in adenomas (P < 0.05). The 5 mutations consisted of 1 frameshift, 1 nonsense mutation, and 3 missense mutations. We expressed the 5 tumor-derived caspase-8 mutants and found that 3 of the 5 mutations markedly decreased apoptosis activity of caspase-8. Furthermore, expression of the inactivating caspase-8 mutants interfered with apoptosis by death receptor overexpression, indicating that these mutants have dominant-negative inhibition of the death receptor-induced apoptosis.
Conclusions:
The presence of caspase-8 mutation in colon carcinomas suggests that caspase-8 gene mutation might lead to the loss of its apoptotic function and contribute to the pathogenesis of colorectal carcinomas, especially at the late stage of colorectal carcinogenesis.
Insights
Caspase-8 gene mutations were found in 5.1% of invasive colorectal carcinomas but not in adenomas, suggesting a role in late-stage colorectal cancer development.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Dysregulation of apoptosis is implicated in cancer pathogenesis.
- Caspase-8 is a key initiator caspase in the apoptosis cascade.
Purpose of the Study:
- To investigate the potential involvement of caspase-8 gene mutations in colorectal cancer development.
Main Methods:
- Analysis of the entire coding region of the caspase-8 gene in 180 colorectal tumors (98 carcinomas, 82 adenomas).
- Utilized polymerase chain reaction, single-strand conformation polymorphism, and DNA sequencing to detect somatic mutations.
Main Results:
- Five somatic mutations were identified in 5.1% of invasive colorectal carcinomas; no mutations were found in adenomas.
- Three of the five identified mutations significantly reduced caspase-8's apoptosis activity.
- These inactivating mutants demonstrated dominant-negative inhibition of death receptor-induced apoptosis.
Conclusions:
- Caspase-8 gene mutations in colon carcinomas suggest a loss of apoptotic function.
- These mutations may contribute to the pathogenesis of colorectal carcinomas, particularly in late-stage carcinogenesis.
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