title: Caspase-8 gene is frequently inactivated by the frameshift somatic mutation 1225_1226delTG in hepatocellular carcinomas.
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.
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
authors.forename: Young Hwa
authors.initials: YH
authors.lastname: Soung
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Yong Jik
authors.initials: YJ
authors.lastname: Sung
authors.forename: Won Sang
authors.initials: WS
authors.lastname: Park
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Kim
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Nam Jin
authors.initials: NJ
authors.lastname: Yoo
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000483:Alleles; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D053181:Caspase 8; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D016368:Frameshift Mutation; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D011485:Protein Binding
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases