Genetic analysis of lung cancer and the germline impact on somatic mutation burden

Autor: Gabriel, AAG, Atkins, JR, Penha, RCC, Smith-Byrne, K, Gaborieau, V, Voegele, C, Abedi-Ardekani, B, Milojevic, M, Olaso, R, Meyer, V, Boland, A, Deleuze, JF, Zaridze, D, Mukeriya, A, Swiatkowska, B, Janout, V, Schejbalová, M, Mates, D, Stojšić, J, Ognjanovic, M, consortium, ILCCO, Witte, JS, Rashkin, SR, Kachuri, L, Hung, RJ, Kar, S, Brennan, P, Sertier, A-S, Ferrari, A, Viari, A, Johansson, M, Amos, CI, Foll, M, McKay, JD
Přispěvatelé: Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), University of Oxford, Université Paris-Saclay, N.N. Blokhin Russian Cancer Research Center, Nofer Institute of Occupational Medicine (NIOM), Palacky University Olomouc, Charles University [Prague] (CU), National Institute of Public Health [Romania] (INSP), University Clinical Centre of Serbia, International Organisation for Cancer Prevention and Research, University of California [San Francisco] (UC San Francisco), University of California (UC), St Jude Children's Research Hospital, Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada, University of Bristol [Bristol], Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Inria Lyon, Institut National de Recherche en Informatique et en Automatique (Inria), Baylor College of Medicine (BCM), Baylor University
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Gabriel, A A G, Atkins, J R, Penha, R C C, Smith Byrne, K, Kar, S, McKay, J D & et, A 2022, ' Genetic analysis of lung cancer and the germline impact on somatic mutation burden ', Journal of the National Cancer Institute, vol. 114, no. 8, pp. 1159-1166 . https://doi.org/10.1093/jnci/djac087
JNCI: Journal of the National Cancer Institute
JNCI: Journal of the National Cancer Institute, 2022, 114 (8), pp.1159-1166. ⟨10.1093/jnci/djac087⟩
ISSN: 0027-8874
1460-2105
Popis: Background 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. Methods 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. Results 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 Conclusions 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.
Databáze: OpenAIRE
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