Alterations of Fas-pathway genes associated with nodal metastasis in non-small cell lung cancer.
Many types of cancer cells are resistant to Fas-mediated apoptosis by several mechanisms, including the mutations of the genes involved in Fas-mediated apoptosis. In this study, to explore the possibility that the mutations of the genes involved in the proximal pathway of Fas-mediated apoptosis (Fas, FADD, caspase 8 and caspase 10) are involved in cancer metastasis, we have analysed somatic mutation and deletion of these genes in 80 non-small cell lung cancers (NSCLCs) with (n=43) and without (n=37) metastasis to the regional lymph nodes. We found 12 mutations (four Fas, four FADD, and four caspase 10 mutations) in 11 of 80 NSCLCs (13.8%). Interestingly, of these mutations, most mutations (10 out of 12) were detected in the NSCLCs with metastasis, and the frequency in the metastasis lesions (23%) was higher than that in the primary lesions of the NSCLCs without metastasis (5.4%). Furthermore, transfection study revealed that the tumor-derived mutants have decreased apoptosis inductions compared to the wild types. These data suggest that the inactivating mutations of the genes in the proximal pathway of Fas-mediated apoptosis may lead to a decreased cancer cell death and play a role in the metastasis of NSCLC.
Shin
Min Sun
MS
Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
Kim
Hong Sug
HS
Lee
Sug Hyung
SH
Lee
Jong Woo
JW
Song
Young Hwa
YH
Kim
Young Sill
YS
Park
Won Sang
WS
Kim
Su Young
SY
Lee
Shi Nae
SN
Park
Jik Young
JY
Lee
Jong Heun
JH
Xiao
Wensua
W
Jo
Keon Hyon
KH
Wang
Young Pil
YP
Lee
Kyo Young
KY
Park
Yong Gyu
YG
Kim
Sang Ho
SH
Lee
Jung Young
JY
Yoo
Nam Jin
NJ
D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics*; D017931:DNA Primers; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008207:Lymphatic Metastasis / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D019014:fas Receptor / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D017931:DNA Primers; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D019014:fas Receptor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053455:Caspase 10; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C506438:CASP10 protein, human