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 cancer (NSCLC), we performed a consistency meta-analysis study utilizing genome-wide association approaches for overall survival in 327 never smoker NSCLC patients from the MD Anderson Cancer Center and 293 cases from the Mayo Clinic. We then performed a two-pronged validation of the top 25 variants that included additional validation in 1,256 NSCLC patients 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%CI:1.01-2.06) and rs10766739 (HR:1.23, 95%CI:1.00-1.51). These loci resulted in a reduction in median survival time of at least 8 and 5 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. These findings identify several novel, candidate prognostic markers for NSCLC in never smokers, with eQTL analysis suggesting a potential biological mechanism for a subset of these observed associations.

The Next-Generation Sequencing Revolution and Its Impact on Genomics

“…To deal with the aforementioned challenge, all of these types of tests share the common feature that they group or collapse rare variation, usually by gene, in order to increase statistical power (see Wu et al, 2013 for a recent review). Early tests (such as the cohort allelic sums test [Morgenthaler and Thilly, 2007] and the combined multivariate collapsing method [Li and Leal, 2008]) assumed that each variant had the same direction of effect and, in addition, required a fixed minor allele frequency cutoff to define which variants to include; but these assumptions are not always valid or optimal.…”

Germline polymorphisms and survival of lung adenocarcinoma patients: A genome‐wide study in two European patient series

“…A recent trend in cancer research is to shift the focus of the search for prognostic markers from the tumoral DNA to the germline DNA, based on the realization that genetic polymorphisms can modulate the risk of developing certain types of cancer and even influence the prognosis . In lung cancer, several studies have tested candidate single nucleotide polymorphisms (SNPs) in association with disease prognosis, but only a few studies used a genome‐wide design . However, these studies included patients with all forms of nonsmall cell lung cancer, without taking into account the different histological subtypes despite the fact that histological type is a determinant of survival .…”

“…11,12 In lung cancer, several studies have tested candidate single nucleotide polymorphisms (SNPs) in association with disease prognosis, but only a few studies used a genome-wide design. 13,14 However, these studies included patients with all forms of nonsmall cell lung cancer, without taking into account the different histological subtypes despite the fact that histological type is a determinant of survival. 15,16 Therefore, it could be useful to analyze a single histotype of lung cancer for genetic determinants of survival.…”

Genetic Variants of the MDM2 Gene Are Predictive of Treatment-Related Toxicities and Overall Survival in Patients With Advanced NSCLC

“…Recently, genome-wide studies were conducted to investigate the association of SNPs with OS in patients with advanced NSCLC; however, no significant association was reported for SNPs in MDM2. [51][52][53][54][55] These results suggested that SNPs in MDM2 might have only limited effects on the survival of patients with advanced NSCLC. The inconsistencies among different studies might have resulted from the heterogeneity among the studies (eg, different tumor cell grade of differentiation, smoking cessation, dietary supplements, or genetic variations).…”