Inactivating mutations of the caspase-10 gene in gastric cancer.
We have analysed the genetic alteration of the entire coding region and all splice sites of caspase-8 and -10 genes in 99 gastric cancers by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) and sequencing. We found LOH of the caspase-8 and -10 in nine (28%) of 32 and in four (15%) of 26 informative cases, respectively. Overall, three of 99 gastric cancers (3%) were found to have the caspase-10 mutations, which were identified in the coding regions of the death effector domain (codon 147) and the p17 large protease domain (codons 257 and 410), whereas no mutation was detected in caspase-8. In vitro expression studies, the M147T and Q257stop mutants severely impaired caspase-10-mediated apoptosis, whereas the V410I which was the same mutation detected in ALPS patient had a significant, albeit less severe, effect on apoptosis. The data presented here suggest that somatic alterations of the caspase-10 gene might contribute to the pathogenesis in a subset of gastric cancers through the loss of their apoptotic function.
Park
Won Sang
WS
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
Lee
Jong Heun
JH
Shin
Min Sun
MS
Park
Jik Young
JY
Kim
Hong Sug
HS
Lee
Jong Ho
JH
Kim
Young Sil
YS
Lee
Shi Nae
SN
Xiao
Wenhua
W
Park
Cho Hyun
CH
Lee
Sug Hyung
SH
Yoo
Nam Jin
NJ
Lee
Jung Young
JY
D000483:Alleles; D017209:Apoptosis; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics*; D002460:Cell Line; D006801:Humans; D016296:Mutagenesis; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C506438:CASP10 protein, human