Inactivating mutations of caspase-8 gene in colorectal carcinomas.
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.
Kim
Hong Sug
HS
Department of Pathaology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Lee
Jong Woo
JW
Soung
Young Hwa
YH
Park
Won Sang
WS
Kim
Su Young
SY
Lee
Jong Heun
JH
Park
Jik Young
JY
Cho
Youg Gu
YG
Kim
Chang Jae
CJ
Jeong
Seong Whan
SW
Nam
Suk Woo
SW
Kim
Sang Ho
SH
Lee
Jung Young
JY
Yoo
Nam Jin
NJ
Lee
Sug Hyung
SH
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
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