title: Inactivating mutations of caspase-8 gene in colorectal carcinomas.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pathaology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hong Sug
authors.initials: HS
authors.lastname: Kim
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Young Hwa
authors.initials: YH
authors.lastname: Soung
authors.forename: Won Sang
authors.initials: WS
authors.lastname: Park
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Jong Heun
authors.initials: JH
authors.lastname: Lee
authors.forename: Jik Young
authors.initials: JY
authors.lastname: Park
authors.forename: Youg Gu
authors.initials: YG
authors.lastname: Cho
authors.forename: Chang Jae
authors.initials: CJ
authors.lastname: Kim
authors.forename: Seong Whan
authors.initials: SW
authors.lastname: Jeong
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; D000483:Alleles; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D009154:Mutation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases