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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.

SUBMITTER: Wu X

PROVIDER: S-EPMC3719971 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers.

Wu Xifeng X Wang Liang L Ye Yuanqing Y Aakre Jeremiah A JA Pu Xia X Chang Gee-Chen GC Yang Pan-Chyr PC Roth Jack A JA Marks Randolph S RS Lippman Scott M SM Chang Joe Y JY Lu Charles C Deschamps Claude C Su Wu-Chou WC Wang Wen-Chang WC Huang Ming-Shyan MS Chang David W DW Li Yan Y Pankratz V Shane VS Minna John D JD Hong Waun Ki WK Hildebrandt Michelle A T MA Hsiung Chao Agnes CA Yang Ping P

Cancer research 20130523 13

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 ...[more]

PMID: 23704207

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Project description:IntroductionLung cancer is the predominant cause of death among cancer patients and non-small cell lung cancer (NSCLC) is the most common type. Cigarette smoking is the prevailing risk factor for NSCLC, nevertheless, this cancer is also diagnosed in never-smokers. B and T lymphocyte attenuator (BTLA) belongs to immunological checkpoints which are key regulatory molecules of the immune response. A growing body of evidence highlights the important role of BTLA in cancer. In our previous studies, we showed a significant association between BTLA gene variants and susceptibility to chronic lymphoblastic leukemia and renal cell carcinoma in the Polish population. The present study aimed to analyze the impact of BTLA polymorphic variants on the susceptibility to NSCLC and NSCLC patients' overall survival (OS).MethodsUsing TaqMan probes we genotyped seven BTLA single-nucleotide polymorphisms (SNPs): rs2705511, rs1982809, rs9288952, rs9288953, rs1844089, rs11921669 and rs2633582 with the use of ViiA 7 Real-Time PCR System.ResultsWe found that rs1982809 within BTLA is associated with NSCLC risk, where carriers of rs1982809G allele (AG+GG genotypes) were more frequent in patients compared to controls. In subgroup analyses, we also noticed that rs1982809G carriers are significantly overrepresented in never-smokers, but not in smokers compared to controls. Additionally, the global distribution of the haplotypes differed between the never-smokers and smokers, where haplotypes A G G C A, C G A C G, and C G A T G were more frequent in never-smoking patients. Furthermore, the presence rs1982809G (AG+GG genotypes) allele as well as the presence of rs9288953T allele (CT+TT genotypes) increased NSCLC risk in females' patients. After stratification by histological type, we noticed that rs1982809G and rs2705511C carriers were more frequent among adenocarcinoma patients. Moreover, rs1982809G and rs2705511C correlated with the more advanced stages of NSCLC (stage II and III), but not with stage IV. Furthermore, we showed that rs2705511 and rs1982809 significantly modified OS, while rs9288952 tend to be associated with patients' survival.ConclusionOur results indicate that BTLA polymorphic variants may be considered low penetrating risk factors for NSCLC especially in never-smokers, and in females, and are associated with OS of NSCLC patients.

Dataset Information

Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers.

Publications

Genome-wide association study of genetic predictors of overall survival for non-small cell lung cancer in never smokers.

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