title: CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas.
abstract: Several lines of evidence indicate that deregulation of apoptosis is involved in the mechanisms of cancer development. Caspase-8 activation plays a central role in the initiation phase of apoptosis. The aim of this study was to explore the possibility that genetic alteration of CASPASE-8 gene is involved in the development of human cancers, including gastric cancers. We have analyzed the entire coding region of human CASPASE-8 gene for the detection of somatic mutations in 162 gastric carcinomas (40 early and 122 advanced cancers), 185 non-small cell lung cancers, 93 breast carcinomas, and 88 acute leukemias by PCR-single-strand conformation polymorphism. Of the cancers analyzed, 13 cancers harbored CASPASE-8 somatic mutations. Interestingly, all of the mutations were detected in the advanced gastric cancers (10.7% of the 122 samples). We expressed the tumor-derived caspase-8 mutants in 293T, 293, and HT1080 cells and found that most of the mutants (9 of the 10 mutations tested) markedly decreased the cell death activity of caspase-8. In addition, in the cells with the inactivating caspase-8 mutants, cleavage of poly(ADP-ribose)polymerase was markedly reduced compared with that of wild-type caspase-8. The occurrence of CASPASE-8 mutation and the inactivation of cell death activity by the mutants suggest that CASPASE-8 gene mutation may affect the pathogenesis of gastric cancers, especially at the late stage of gastric carcinogenesis.
authors.affiliation: Department of Pathology, College of Medicine, Catholic University of Korea, 505 Banpo-dong, Socho-gu, 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: Jin
authors.initials: J
authors.lastname: Jang
authors.forename: Yong Gyu
authors.initials: YG
authors.lastname: Park
authors.forename: Won Sang
authors.initials: WS
authors.lastname: Park
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
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; D053181:Caspase 8; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D009154:Mutation; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
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