Protein-altering germline mutations implicate novel genes related to lung cancer development

Abstract

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10−15) and replication (adjusted OR = 2.93, P = 2.22 × 10−3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10−22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

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Item Type:	Article
Authors/Creators:	Ji, X Mukherjee, S Landi, MT Bosse, Y Joubert, P Zhu, D Gorlov, I Xiao, X Han, Y Gorlova, O Hung, RJ Brhane, Y Carreras-Torres, R Christiani, DC Caporaso, N Johansson, M Liu, G Bojesen, SE Le Marchand, L Albanes, D Bickeböller, H Aldrich, MC Bush, WS Tardon, A Rennert, G Chen, C Byun, J Dragnev, KH Field, JK Kiemeney, LFA Lazarus, P Zienolddiny, S Lam, S Schabath, MB Andrew, AS Bertazzi, PA Pesatori, AC Diao, N Su, L Song, L Zhang, R Leighl, N Johansen, JS Mellemgaard, A Saliba, W Haiman, C Wilkens, L Fernandez-Somoano, A Fernandez-Tardon, G Heijden, EHFMVD Kim, JH Davies, MPA Marcus, MW Brunnström, H Manjer, J Melander, O Muller, DC Overvad, K Trichopoulou, A Tumino, R Goodman, GE Cox, A https://orcid.org/0000-0002-5138-1099 Taylor, F Woll, P https://orcid.org/0000-0002-1118-0831 Wichmann, E Muley, T Risch, A Rosenberger, A Grankvist, K Johansson, M Shepherd, F Tsao, M-S Arnold, SM Haura, EB Bolca, C Holcatova, I Janout, V Kontic, M Lissowska, J Mukeria, A Ognjanovic, S Orlowski, TM Scelo, G Swiatkowska, B Zaridze, D Bakke, P Skaug, V Butler, LM Offit, K Srinivasan, P Bandlamudi, C Hellmann, MD Solit, DB Robson, ME Rudin, CM Stadler, ZK Taylor, BS Berger, MF Houlston, R McLaughlin, J Stevens, V Nickle, DC Obeidat, M Timens, W Artigas, MS Shete, S Brenner, H Chanock, S Brennan, P McKay, JD Amos, CI
Copyright, Publisher and Additional Information:	© 2020 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 25 March 2020 Published (online): 11 May 2020 Published: December 2020
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
Funding Information:	Funder Grant number Cancer Research UK C43420/A17904; C5410/A7315; C5410/A15588 National Institute for Health Research ECMC Sheffield Teaching Hospitals NHS Foundation Trust N/A Sheffield Hospitals Charitable Trust 091002 Weston Park Hospital Cancer Charity CA115 Sheffield Hospitals Charitable Trust (Special Trustees) 091002
Depositing User:	Symplectic Sheffield
Date Deposited:	27 May 2020 10:56
Last Modified:	27 May 2020 11:27
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/s41467-020-15905-6
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:161227

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Protein-altering germline mutations implicate novel genes related to lung cancer development

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