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 1,185 NSCLC patients using a dataset from Prostate, Lung, Colorectal and Ovarian (PLCO) 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 from 984 NSCLC patients in Harvard Lung Cancer Susceptibility (HLCS) Study. Finally, two independent SNPs (HBEGF rs4150236G>A and ITPR3 rs116454384C>T) remained significantly associated with NSCLC OS with a combined hazards ratio 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 (DSS) (P=0.0002 and 0.0001, respectively). Further expression quantitative trail loci analysis showed significant correlations between ITPR3 rs116454384T genotypes and higher mRNA expression levels in both whole blood and normal lung; high ITPR3 mRNA expression levels in tumors was 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 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.
Copyright © 2021. Published by Elsevier Inc.