title: Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers.
abstract: To identify the genetic factors that influence overall survival in never smokers who have non-small cell lung carcinoma (NSCLC), we conducted a consistency meta-analysis study using genome-wide association approaches for overall survival in 327 never smoker patients with NSCLC from The University of Texas MD Anderson Cancer Center (Houston, TX) and 293 cases from the Mayo Clinic (Rochester, MN). We then conducted a two-pronged validation of the top 25 variants that included additional validation in 1,256 patients with NSCLC from Taiwan and assessment of expression quantitative trait loci (eQTL) and differential expression of genes surrounding the top loci in 70 tumors and matched normal tissues. A total of 94 loci were significant for overall survival in both MD Anderson and Mayo studies in the consistency meta-analysis phase, with the top 25 variants reaching a P value of 10(-6). Two variants of these 25 were also significant in the Taiwanese population: rs6901416 [HR, 1.44; 95% confidence interval (CI), 1.01-2.06] and rs10766739 (HR, 1.23; 95%CI, 1.00-1.51). These loci resulted in a reduction of median survival time of at least eight and five months in three populations, respectively. An additional six variants (rs4237904, rs7976914, rs4970833, rs954785, rs485411, and rs10906104) were validated through eQTL analysis that identified significant correlations with expression levels of six genes (LEMD3, TMBIM, ATXN7L2, SHE, ITIH2, and NUDT5, respectively) in normal lung tissue. These genes were also significantly differentially expressed between the tumor and normal lung tissue. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biologic mechanism for a subset of these observed associations.
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. xwu@mdanderson.org
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.forename: Jeremiah A
authors.initials: JA
authors.lastname: Aakre
authors.forename: Xia
authors.initials: X
authors.lastname: Pu
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Marks
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: Joe Y
authors.initials: JY
authors.lastname: Chang
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.forename: Claude
authors.initials: C
authors.lastname: Deschamps
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Wang
authors.forename: Ming-Shyan
authors.initials: MS
authors.lastname: Huang
authors.forename: David W
authors.initials: DW
authors.lastname: Chang
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.forename: Chao Agnes
authors.initials: CA
authors.lastname: Hsiung
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality; D052138:Genes, Neoplasm; D055106:Genome-Wide Association Study; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012907:Smoking