Inactivating mutations of caspase-8 gene in colorectal carcinomas

Gastroenterology. 2003 Sep;125(3):708-15. doi: 10.1016/s0016-5085(03)01059-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Alleles
  • Apoptosis
  • Carrier Proteins / metabolism
  • Caspase 8
  • Caspase 9
  • Caspases / genetics*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA Methylation
  • Fas-Associated Death Domain Protein
  • Humans
  • Mutation*


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases