FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer.
The FAS receptor-ligand system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumor-immune escape and carcinogenesis. We have recently demonstrated (Sun, T., X. Miao, X. Zhang, W. Tan, P. Xiong, and D. Lin. 2004. J. Natl. Cancer Inst. 96:1030-1036; Zhang, X., X. Miao, T. Sun, W. Tan, S. Qu, P. Xiong, Y. Zhou, and D. Lin. 2005. J. Med. Genet. 42:479-484) that functional polymorphisms in FAS and FAS ligand (FASL) are associated with susceptibility to lung cancer and esophageal cancer; however, the mechanisms underlying this association have not been elucidated. We show that the FAS -1377G, FAS -670A, and FASL -844T variants are expressed more highly on ex vivo-stimulated T cells than the FAS -1377A, FAS -670G, and FASL -844C variants. Moreover, activation-induced cell death (AICD) of T cells carrying the FASL -844C allele was increased. We also found a threefold increased risk of cervical cancer among subjects with the FASL -844CC genotype compared with those with the -844TT genotype in a case-control study in Chinese women. Together, these observations suggest that genetic polymorphisms in the FAS-FASL pathway confer host susceptibility to cervical cancers, which might be caused by immune escape of tumor cells because of enhanced AICD of tumor-specific T cells.
Sun
Tong
T
Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, China.
Zhou
Yifeng
Y
Li
Hua
H
Han
Xiaohong
X
Shi
Yuankai
Y
Wang
Li
L
Miao
Xiaoping
X
Tan
Wen
W
Zhao
Dan
D
Zhang
Xuemei
X
Guo
Yongli
Y
Lin
Dongxin
D
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D016022:Case-Control Studies; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002681:China; D003520:Cyclophosphamide; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D015810:Linkage Disequilibrium; D008558:Melphalan; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012673:Semustine; D013601:T-Lymphocytes / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000276:immunology
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D012673:Semustine; D003520:Cyclophosphamide; D008558:Melphalan