Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers
Journal
Cancer research
Journal Volume
73
Journal Issue
13
Pages
4028
Date Issued
2013-07-01
Author(s)
Wu, Xifeng
Wang, Liang
Ye, Yuanqing
Aakre, Jeremiah A
Pu, Xia
Chang, Gee-Chen
Roth, Jack A
Marks, Randolph S
Lippman, Scott M
Chang, Joe Y
Lu, Charles
Deschamps, Claude
Su, Wu-Chou
Wang, Wen-Chang
Huang, Ming-Shyan
Chang, David W
Li, Yan
Pankratz, V Shane
Minna, John D
Hong, Waun Ki
Hildebrandt, Michelle A T
Hsiung, Chao Agnes
Yang, Ping
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.
Subjects
SUSCEPTIBILITY LOCUS; PROMOTER METHYLATION; ABERRANT METHYLATION; TOBACCO-SMOKE; MUTATIONS; DISEASE; COMMON; EPHA7; RISK; HYPERMETHYLATION
SDGs
Publisher
AMER ASSOC CANCER RESEARCH
Type
journal article