Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden.
Genetic Analysis of Lung Cancer and the Germline Impact on Somatic Mutation Burden.
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DOI：
10.1093/jnci/djac087
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发表时间：
2022-08-08
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生殖系遗传变异有助于肺癌（LC）的易感性。以前的全基因组关联研究（GWAS）涉及吸烟行为和DNA修复基因的易感位点，但需要进一步的工作来确定易感性变异。为了确定LC易感基因座，通过荟萃分析将基于家族史的LC全基因组代理关联（GWAX）（48 843例欧洲代理LC患者，195 387例对照）与既往LC GWAS（29 266例患者，56 450例对照）相结合。共定位被用来探索候选基因，并与已发现的易感基因座上的现有性状重叠。在一个独立的验证队列（1 666例LC患者和6 664例对照）中，使用从LC易感基因座中选择的变异和使用已发表的GWAS汇总统计量的新选择方法，对多基因风险评分（PRS）进行了测试。最后，在已经通过外显子组（n = 685）和基因组测序（n = 61）分析肿瘤切除的患者中探索LC PRS对体细胞突变负荷的影响。统计检验为双侧检验。GWAx-GWAS荟萃分析确定了8个新的LC基因座。共定位涉及DNA修复基因（CHEK 1）、代谢基因（CYP 1A 1）和吸烟倾向基因（CHRNA 4和CHRNB 2）。PRS分析表明，这些变异，以及与表达数量性状基因座和/或吸烟倾向相关的亚基因组显著变异，有助于LC遗传风险预测（比值比= 1.37，95%置信区间= 1.29至1.45; P < .001）。具有较高吸烟相关变异的遗传PRS负荷的患者倾向于在其肺肿瘤中具有较高的突变负荷。这项研究扩大了LC易感基因座的数量，并提供了深入了解这些易感性变异有助于LC发展的分子机制。
Germline genetic variation contributes to lung cancer (LC) susceptibility. Previous genome-wide association studies (GWAS) have implicated susceptibility loci involved in smoking behaviors and DNA repair genes, but further work is required to identify susceptibility variants. To identify LC susceptibility loci, a family history-based genome-wide association by proxy (GWAx) of LC (48 843 European proxy LC patients, 195 387 controls) was combined with a previous LC GWAS (29 266 patients, 56 450 controls) by meta-analysis. Colocalization was used to explore candidate genes and overlap with existing traits at discovered susceptibility loci. Polygenic risk scores (PRS) were tested within an independent validation cohort (1 666 LC patients vs 6 664 controls) using variants selected from the LC susceptibility loci and a novel selection approach using published GWAS summary statistics. Finally, the effects of the LC PRS on somatic mutational burden were explored in patients whose tumor resections have been profiled by exome (n = 685) and genome sequencing (n = 61). Statistical tests were 2-sided. The GWAx–GWAS meta-analysis identified 8 novel LC loci. Colocalization implicated DNA repair genes (CHEK1), metabolic genes (CYP1A1), and smoking propensity genes (CHRNA4 and CHRNB2). PRS analysis demonstrated that these variants, as well as subgenome-wide significant variants related to expression quantitative trait loci and/or smoking propensity, assisted in LC genetic risk prediction (odds ratio = 1.37, 95% confidence interval = 1.29 to 1.45; P < .001). Patients with higher genetic PRS loads of smoking-related variants tended to have higher mutation burdens in their lung tumors. This study has expanded the number of LC susceptibility loci and provided insights into the molecular mechanisms by which these susceptibility variants contribute to LC development.
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影响因子：
30.8
作者：
McKay, James D.;Hung, Rayjean J.;Gaborieau, Valerie;Boffetta, Paolo;Chabrier, Amelie;Byrnes, Graham;Zaridze, David;Mukeria, Anush;Szeszenia-Dabrowska, Neonilia;Lissowska, Jolanta;Rudnai, Peter;Fabianova, Eleonora;Mates, Dana;Bencko, Vladimir;Foretova, Lenka;Janout, Vladimir;McLaughlin, John;Shepherd, Frances;Montpetit, Alexandre;Narod, Steven;Krokan, Hans E.;Skorpen, Frank;Elvestad, Maiken Bratt;Vatten, Lars;Njolstad, Inger;Axelsson, Tomas;Chen, Chu;Goodman, Gary;Barnett, Matt;Loomis, Melissa M.;Lubinski, Jan;Matyjasik, Joanna;Lener, Marcin;Oszutowska, Dorota;Field, John;Liloglou, Triantafillos;Xinarianos, George;Cassidy, Adrian;Zelenika, Diana;Boland, Anne;Delepine, Marc;Foglio, Mario;Lechner, Doris;Matsuda, Fumihiko;Blanche, Helene;Gut, Ivo;Heath, Simon;Lathrop, Mark;Brennan, Paul
通讯作者：
Brennan, Paul
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
30.8
作者：
Melin BS;Barnholtz-Sloan JS;Wrensch MR;Johansen C;Il'yasova D;Kinnersley B;Ostrom QT;Labreche K;Chen Y;Armstrong G;Liu Y;Eckel-Passow JE;Decker PA;Labussière M;Idbaih A;Hoang-Xuan K;Di Stefano AL;Mokhtari K;Delattre JY;Broderick P;Galan P;Gousias K;Schramm J;Schoemaker MJ;Fleming SJ;Herms S;Heilmann S;Nöthen MM;Wichmann HE;Schreiber S;Swerdlow A;Lathrop M;Simon M;Sanson M;Andersson U;Rajaraman P;Chanock S;Linet M;Wang Z;Yeager M;GliomaScan Consortium;Wiencke JK;Hansen H;McCoy L;Rice T;Kosel ML;Sicotte H;Amos CI;Bernstein JL;Davis F;Lachance D;Lau C;Merrell RT;Shildkraut J;Ali-Osman F;Sadetzki S;Scheurer M;Shete S;Lai RK;Claus EB;Olson SH;Jenkins RB;Houlston RS;Bondy ML
通讯作者：
Bondy ML
影响因子：
11.2
作者：
Hung RJ;Warkentin MT;Brhane Y;Chatterjee N;Christiani DC;Landi MT;Caporaso NE;Liu G;Johansson M;Albanes D;Marchand LL;Tardon A;Rennert G;Bojesen SE;Chen C;Field JK;Kiemeney LA;Lazarus P;Zienolddiny S;Lam S;Andrew AS;Arnold SM;Aldrich MC;Bickeböller H;Risch A;Schabath MB;McKay JD;Brennan P;Amos CI
通讯作者：
Amos CI
影响因子：
9.2
作者：
Choi, Shing Wan;O'Reilly, Paul F.
通讯作者：
O'Reilly, Paul F.