Dataset Information

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.

ABSTRACT:

Background

Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer.

Methods

We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer.

Results

Five novel independent loci, GABRA4, intergenic region 12q24.33, LRRC4C, LINC01088, and LCNL1 were identified with the association at two or three populations (P < 5 × 10-8). Further functional analysis provided multiple lines of evidence suggesting the variants affect lung cancer risk through excessive DNA damage (GABRA4) or cis-regulation of gene expression (LCNL1). The risk of variants from 12 independent regions, including the well-known CHRNA5, associated with ever-smoking lung cancer was evaluated for never-smokers, light-smokers (packyear ≤ 20), and moderate-to-heavy-smokers (packyear > 20). Different risk patterns were observed for the variants among the different groups by smoking behavior.

Conclusions

We identified novel variants associated with lung cancer in only ever- or never-smoking groups that were missed by prior main-effect association studies.

Impact

Our study highlights the genetic heterogeneity between ever- and never-smoking lung cancer and provides etiologic insights into the complicated genetic architecture of this deadly cancer.

SUBMITTER: Li Y

PROVIDER: S-EPMC10905670 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.

Li Yafang Y Xiao Xiangjun X Li Jianrong J Han Younghun Y Cheng Chao C Fernandes Gail F GF Slewitzke Shannon E SE Rosenberg Susan M SM Zhu Meng M Byun Jinyoung J Bossé Yohan Y McKay James D JD Albanes Demetrios D Lam Stephen S Tardon Adonina A Chen Chu C Bojesen Stig E SE Landi Maria T MT Johansson Mattias M Risch Angela A Bickeböller Heike H Wichmann H-Erich HE Christiani David C DC Rennert Gad G Arnold Susanne M SM Goodman Gary E GE Field John K JK Davies Michael P A MPA Shete Sanjay S Marchand Loïc Le LL Liu Geoffrey G Hung Rayjean J RJ Andrew Angeline S AS Kiemeney Lambertus A LA Sun Ryan R Zienolddiny Shanbeh S Grankvist Kjell K Johansson Mikael M Caporaso Neil E NE Cox Angela A Hong Yun-Chul YC Lazarus Philip P Schabath Matthew B MB Aldrich Melinda C MC Schwartz Ann G AG Gorlov Ivan I Purrington Kristen S KS Yang Ping P Liu Yanhong Y Bailey-Wilson Joan E JE Pinney Susan M SM Mandal Diptasri D Willey James C JC Gaba Colette C Brennan Paul P Xia Jun J Shen Hongbing H Amos Christopher I CI

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20240301 3

<h4>Background</h4>Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer.<h4>Methods</h4>We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage ass ...[more]

PMID: 38180474

Similar Datasets

Project description:BackgroundTobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile.MethodsWe conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment.ResultsOur findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1.ConclusionsWe found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.

Dataset Information

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.

Background

Methods

Results

Conclusions

Impact

Publications

Lung Cancer in Ever- and Never-Smokers: Findings from Multi-Population GWAS Studies.

Similar Datasets

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