Inactivating mutations of KILLER/DR5 gene in gastric cancers.
OBJECTIVE
The KILLER/death receptor (DR)5 has been identified as a potent inducer of apoptosis, and mapped to chromosome 8p21-22, showing frequent allelic loss in gastric cancer. The p53-induced apoptosis is an important biological process to prevent the development of cancer, and is mediated in part by expression of KILLER/DR5 only in cells with wild-type p53 protein, but not in those lacking p53 function. The aim of this study was to determine whether genetic alterations of KILLER/DR5 could be involved in the tumorigenesis of gastric cancer.


METHODS
We analyzed the genetic alterations of KILLER/DR5 and p53 in 43 gastric cancers and the loss of function of KILLER/DR5 mutants, detected in this study.


RESULTS
We found 3 KILLER/DR5 missense mutations (7%), and 2 of them showed allelic loss in the remaining allele. Interestingly, all the mutants inhibit apoptotic cell death in transfection studies. We also found 6 p53 mutations (14%). Interestingly, the tumors containing the KILLER/DR5 mutation did not carry the p53 mutation.


CONCLUSIONS
These results suggest that inactivation of KILLER/DR5 caused by mutations of KILLER/DR5 may be one of the possible escaping mechanisms against KILLER/DR5-mediated apoptosis and that inactivating mutation of KILLER/DR5 may contribute to the development or progression of a subset of gastric cancers.
Park
W S
WS
Department of Pathology, College of Medicine, The Catholic University of Korea.
Lee
J H
JH
Shin
M S
MS
Park
J Y
JY
Kim
H S
HS
Kim
Y S
YS
Park
C H
CH
Lee
S K
SK
Lee
S H
SH
Lee
S N
SN
Kim
H
H
Yoo
N J
NJ
Lee
J Y
JY
D000483:Alleles; D002460:Cell Line; D004249:DNA Damage; D016158:Genes, p53; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics*
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505639:TNFRSF10B protein, human