Dataset Information

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region.

ABSTRACT: INTRODUCTION:Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS:We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS:We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS:We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

SUBMITTER: Hung RJ

PROVIDER: S-EPMC6833942 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5<sub>p</sub>15.33 TERT-CLPTM1Ll Region.

Hung Rayjean J RJ Spitz Margaret R MR Houlston Richard S RS Schwartz Ann G AG Field John K JK Ying Jun J Li Yafang Y Han Younghun Y Ji Xuemei X Chen Wei W Wu Xifeng X Gorlov Ivan P IP Na Jie J de Andrade Mariza M Liu Geoffrey G Brhane Yonathan Y Diao Nancy N Wenzlaff Angela A Davies Michael P A MPA Liloglou Triantafillos T Timofeeva Maria M Muley Thomas T Rennert Hedy H Saliba Walid W Ryan Bríd M BM Bowman Elise E Barros-Dios Juan-Miguel JM Pérez-Ríos Mónica M Morgenstern Hal H Zienolddiny Shanbeh S Skaug Vidar V Ugolini Donatella D Bonassi Stefano S van der Heijden Erik H F M EHFM Tardon Adonina A Bojesen Stig E SE Landi Maria Teresa MT Johansson Mattias M Bickeböller Heike H Arnold Susanne S Le Marchand Loic L Melander Olle O Andrew Angeline A Grankvist Kjell K Caporaso Neil N Teare M Dawn MD Schabath Matthew B MB Aldrich Melinda C MC Kiemeney Lambertus A LA Wichmann H-Erich HE Lazarus Philip P Mayordomo Jose J Neri Monica M Haugen Aage A Zhang Zuo-Feng ZF Ruano-Raviña Alberto A Brenner Hermann H Harris Curtis C CC Orlow Irene I Rennert Gadi G Risch Angela A Brennan Paul P Christiani David C DC Amos Christopher I CI Yang Ping P Gorlova Olga Y OY

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20190419 8

<h4>Introduction</h4>Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer.<h4>Methods</h4>We conducted a two-phase (discovery and replication) genome-wide associatio ...[more]

PMID: 31009812

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Project description:ObjectiveTo prospectively investigate whether diversity in oral microbiota is associated with risk of lung cancer among never-smokers.Design and settingA nested case-control study within two prospective cohort studies, the Shanghai Women's Health Study (n=74 941) and the Shanghai Men's Health Study (n=61 480).ParticipantsLifetime never-smokers who had no cancer at baseline. Cases were subjects who were diagnosed with incident lung cancer (n=114) and were matched 1:1 with controls on sex, age (≤2 years), date (≤30 days) and time (morning/afternoon) of sample collection, antibiotic use during the week before sample collection (yes/no) and menopausal status (for women).Main outcomes and measuresMetagenomic shotgun sequencing was used to measure the community structure and abundance of the oral microbiome in pre-diagnostic oral rinse samples of each case and control. Multivariable logistic regression models were used to estimate the association of lung cancer risk with alpha diversity metrics and relative abundance of taxa. The Microbiome Regression-Based Kernel Association Test (MiRKAT) evaluated the association between risk and the microbiome beta diversity.ResultsSubjects with lower microbiota alpha diversity had an increased risk of lung cancer compared with those with higher microbial alpha diversity (Shannon: ptrend=0.05; Simpson: ptrend=0.04; Observed Species: ptrend=0.64). No case-control differences were apparent for beta diversity (pMiRKAT=0.30). After accounting for multiple comparisons, a greater abundance of Spirochaetia (ORlow 1.00 (reference), ORmedium 0.61 (95% CI 0.32 to 1.18), ORhigh 0.42 (95% CI 0.21 to 0.85)) and Bacteroidetes (ORlow 1.00 (reference), ORmedium 0.66 (95% CI 0.35 to 1.25), ORhigh 0.31 (95% CI 0.15 to 0.64)) was associated with a decreased risk of lung cancer, while a greater abundance of the Bacilli class (ORlow 1.00 (reference), ORmedium 1.49 (95% CI 0.73 to 3.08), ORhigh 2.40 (95% CI 1.18 to 4.87)) and Lactobacillales order (ORlow 1.00 (reference), ORmedium 2.15 (95% CI 1.03 to 4.47), ORhigh 3.26 (95% CI 1.58 to 6.70)) was associated with an increased risk of lung cancer.ConclusionsOur prospective study of never-smokers suggests that lower alpha diversity was associated with a greater risk of lung cancer and the abundance of certain specific taxa was associated with altered risk, providing further insight into the aetiology of lung cancer in the absence of active tobacco smoking.

Dataset Information

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region.

Publications

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5<sub>p</sub>15.33 TERT-CLPTM1Ll Region.

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