Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas

Oncogene. 2005 Jan 6;24(1):141-7. doi: 10.1038/sj.onc.1208244.

Abstract

Evidence exists that alterations of the genes encoding apoptosis-related proteins contribute to either development or progression of human cancers. Caspase-8 plays a crucial role in the initiation phase of apoptosis. To explore the possibility that the genetic alteration of caspase-8 gene is involved in the development of hepatocellular carcinomas (HCCs), we have analysed the entire coding region of human caspase-8 gene for the detection of somatic mutations by polymerase chain reaction-single-strand conformation polymorphism in 69 HCCs with low-grade dysplastic nodule (LGDN, n=2) or high-grade dysplastic nodule (HGDN, n=2) or without any dysplastic nodules (n=65). Overall, we detected a total of nine somatic mutations in 69 HCCs (13.0%). Interestingly, all of the nine mutations were an identical frameshift mutation with two base-pair deletion (1225_1226delTG), which would result in a premature termination of amino-acid synthesis in the p10 protease subunit. In a patient sample, we detected the 1225_1226delTG mutation both in HCC and LDGN lesions, suggesting that caspase-8 mutation could be involved in the early stage of HCC carcinogenesis. We expressed the tumor-derived caspase-8 mutant in the cells and found that the mutant abolished cell death activity of caspase-8. Our data indicate that caspase-8 gene is frequently mutated in HCC and the majority of the mutations may be the frameshift mutation 1225_1226delTG. Also, the data suggest that caspase-8 gene mutation might lead to the loss of its cell death function and contribute to the pathogenesis of HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Alleles
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Caspase 8
  • Caspases / genetics*
  • Caspases / metabolism
  • Fas-Associated Death Domain Protein
  • Frameshift Mutation*
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Organ Specificity
  • Protein Binding

Substances

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