• Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China; Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina; Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina.
• Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina; Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina.
• Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina.
• Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina; Department of Medicine, Duke University Medical Center, Durham, North Carolina.
• Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina; Department of Pathology, Duke University School of Medicine, Durham, North Carolina.
• Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts.
• Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
• Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
• Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. Electronic address: qimingwang1006@126.com.
• Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina; Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina; Department of Medicine, Duke University Medical Center, Durham, North Carolina. Electronic address: qingyi.wei@duke.edu.

The gonadotropin-releasing hormone (GnRH) signaling pathway controls reproductive functions and cancer growth and progression. However, few studies investigated roles of genetic variants of GnRH pathway genes in survival of patients with non-small cell lung cancer (NSCLC). Therefore, we first evaluated associations between 22,528 single-nucleotide polymorphisms (SNPs) in 101 GnRH pathway genes and survival of 1185 NSCLC patients using a dataset from Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We found 572 SNPs to be significantly associated with overall survival (OS) of NSCLC (P ≤ 0.05, Bayesian false discovery probability ≤0.80). We then validated these SNPs in another dataset with 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. Finally, two independent SNPs (HBEGF rs4150236G>A and ITPR3 rs116454384C>T) remained significantly associated with NSCLC OS in the combined analysis with hazards ratios of 0.84 (95% confidence interval = 0.76-0.92, P = 0.0003) and 0.85 (0.78-0.94, 0.0012), respectively; their genetic score (the number of protective genotypes) was associated with a better OS and disease-specific survival (P_trend = 0.0002 and 0.0001, respectively). Further expression quantitative trail loci analysis showed a significant correlation between ITPR3 rs116454384 T allele and an increased mRNA expression level in both whole blood and normal lung tissue, and high ITPR3 mRNA expression levels in tumors were associated with a better survival of NSCLC patients. Because ITPR3 mutations were rare in tumors, ITPR3 rs116454384C>T likely had an effect on cancer progression by regulating the gene expression. Therefore, genetic variants of HBEGF rs4150236G>A and ITPR3 rs116454384C>T may be predictors for NSCLC survival, but HBEGF rs4150236G>A functional relevance remains to be determined.