title: Association of a novel functional promoter variant (rs2075533 C>T) in the apoptosis gene TNFSF8 with risk of lung cancer--a finding from Texas lung cancer genome-wide association study.
abstract: Published genome-wide association studies (GWASs) have identified few variants in the known biological pathways involved in lung cancer etiology. To mine the possibly hidden causal single nucleotide polymorphisms (SNPs), we explored all SNPs in the extrinsic apoptosis pathway from our published GWAS dataset for 1154 lung cancer cases and 1137 cancer-free controls. In an initial association analysis of 611 tagSNPs in 41 apoptosis-related genes, we identified only 10 tagSNPs associated with lung cancer risk with a P value<10(-2), including four tagSNPs in DAPK1 and three tagSNPs in TNFSF8. Unlike DAPK1 SNPs, TNFSF8 rs2181033 tagged other four predicted functional but untyped SNPs (rs776576, rs776577, rs31813148 and rs2075533) in the promoter region. Therefore, we further tested binding affinity of these four SNPs by performing the electrophoretic mobility shift assay. We found that only rs2075533T allele modified levels of nuclear proteins bound to DNA, leading to significantly decreased expression of luciferase reporter constructs by 5- to -10-fold in H1299, HeLa and HCT116 cell lines compared with the C allele. We also performed a replication study of the untyped rs2075533 in an independent Texas population but did not confirm the protective effect. We further performed a mini meta-analysis for SNPs of TNFSF8 obtained from other four published lung cancer GWASs with 12  214 cases and 47  721 controls, and we found that only rs3181366 (r2=0.69 with the untyped rs2075533) was associated to lung cancer risk (P=0.008). Our findings suggest a possible role of novel TNFSF8 variants in susceptibility to lung cancer.
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
authors.forename: Jiangong
authors.initials: J
authors.lastname: Niu
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Zhensheng
authors.initials: Z
authors.lastname: Liu
authors.forename: Li-E
authors.initials: LE
authors.lastname: Wang
authors.forename: Younghun
authors.initials: Y
authors.lastname: Han
authors.forename: Wei V
authors.initials: WV
authors.lastname: Chen
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Amos
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Maria T
authors.initials: MT
authors.lastname: Landi
authors.forename: Neil E
authors.initials: NE
authors.lastname: Caporaso
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thun
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Yufei
authors.initials: Y
authors.lastname: Wang
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D053285:CD30 Ligand / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D017730:Ki-1 Antigen / Q000502:physiology; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012306:Risk; D013781:Texas
chemical_list: D053285:CD30 Ligand; D017730:Ki-1 Antigen; C505774:TNFSF8 protein, human