Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-15905-6
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Categories
Funding
- Cancer Prevention Research Interest of Texas [RR170048]
- National Institutes of Health (NIH) [P30CA023108, P20GM103534]
- Trandisciplinary Research in Cancer of the Lung (TRICL) [U19CA148127]
- Integrative Analysis of Lung Cancer Etiology and Risk US NIH [U19CA203654]
- UICC American Cancer Society Beginning Investigators Fellowship by the Union for International Cancer Control (UICC)
- FIS-FEDER/Spain [FIS-01/310, FIS-PI03-0365, FIS-07-BI060604]
- FICYT/Asturias [FICYT PB02-67, FICYT IB09-133]
- University Institute of Oncology (IUOPA), of the University of Oviedo
- Ciber de Epidemiologia y Salud Publica
- NIH [UM1 CA167462, UO1-CA6367307, CA111703, R01 CA151989, U01 CA167462, CA092824, CA090578, CA074386, CA209414, CA164973, CA033619, CA63464, CA148127]
- Roy Castle Lung Cancer Foundation
- Chief Physician Johan Boserup and Lise Boserup Fund
- Danish Medical Research Council
- Herlev Hospital
- Cancer Prevention & Research Institute of Texas [RP130502]
- University of Texas MD Anderson Cancer Center
- Nofer Institute of Occupational Medicine
- Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] [10153006 (W81XWH-11-1-0781)]
- Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre
- Wellcome Trust Investigator Award [WT202849/Z/16/Z]
- Fondation de l'Institut universitaire de cardiologie et de pneumologie de Quebec
- Respiratory Health Network of the FRQS
- Canadian Institutes of Health Research [MOP -123369]
- National Institute for Health Research (NIHR)
- Medical Research Council [G0902313]
- MRC [G0902313] Funding Source: UKRI
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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=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-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=7.98x10(-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. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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