Resumen
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.
| Idioma original | English |
|---|---|
| Número de artículo | 2220 |
| Publicación | Nature Communications |
| Volumen | 11 |
| N.º | 1 |
| DOI | |
| Estado | Published - dic 1 2020 |
Nota bibliográfica
Publisher Copyright:© 2020, The Author(s).
Financiación
We thank the individuals who have contributed their samples and clinical data for this study and we also thank the members of the International Lung Cancer Consortium, who provided access to samples and clinical data. This work was partially supported by Cancer Prevention Research Interest of Texas award RR170048, which supports Dr. Christopher Amos, a CPRIT Scholar in Cancer Research. Funding for this research has also been provided by the National Institutes of Health (NIH) for core research support in cancer (grant P30CA023108 and P20GM103534); and for lung cancer through the Trandisciplinary Research in Cancer of the Lung (TRICL) (grant U19CA148127) and Integrative Analysis of Lung Cancer Etiology and Risk (U19CA203654) US NIH grants; UICC American Cancer Society Beginning Investigators Fellowship funded by the Union for International Cancer Control (UICC) (to X.J.). The Institut national du Cancer (France) (TABAC 17‐022) supports Dr McKay. The CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03-0365, and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02-67 and FICYT IB09-133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Pública. CIBERESP, SPAIN.CARET study was supported by NIH awards UM1 CA167462, UO1-CA6367307, CA111703, R01 CA151989, and U01 CA167462. The Liverpool Lung project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by NIH grants CA092824, CA090578, CA074386, and CA209414. The Multiethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464, and CA148127. The MSH-PMH study was supported by The Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Cancer Foundation. R.F.T is supported by a Canada Research Chair in Pharmacogenomics, CIHR grant FDN-154294) and CAMH. The TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), NIH grant P50 CA119997 and P30CA76292. The Vanderbilt Lung Cancer Study – BioVU dataset used for the analyses described was obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding, the 1S10RR025141-01 instrumentation award, and by the Vanderbilt CTSA grant UL1TR000445 from NCATS/NIH, K07CA172294, and U01HG004798. The Copenhagen General Population Study was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study was supported by NIH grant P20RR018787. The MDACC study was supported in part by grants from the NIH (P50 CA070907, R01 CA176568), Cancer Prevention & Research Institute of Texas (RP130502), and The University of Texas MD Anderson Cancer Center institutional support for the Center for Translational and Public Health Genomics. The study in Lodz center was partially funded by Nofer Institute of Occupational Medicine, under task NIOM 10.13: Predictors of mortality from non-small cell lung cancer - field study. Kentucky Lung Cancer Research Initiative was supported by the Department of Defense [Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program] under award number: 10153006 (W81XWH-11-1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. It also supported by NIH grant UL1TR000117 and P30 CA177558 using Shared Resource Facilities: Cancer Research Informatics, Biospe-cimen and Tissue Procurement, and Biostatistics and Bioinformatics. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. F.T. was supported by a clinical PhD fellowship funded by the Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre. L.V.W. held a GSK / British Lung Foundation Chair in Respiratory Research and M.D.T. was supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). The authors at Laval would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the lung eQTL dataset at Laval University. The lung eQTL study at Laval University was supported by the Fondation de l’Institut universitaire de cardiologie et de pneumologie de Québec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP - 123369). Y.B. holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The research undertaken by M.D.T., L.V.W., and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer /World Health Organization.
| Financiadores | Número del financiador |
|---|---|
| Sundhed og Sygdom, Det Frie Forskningsråd | |
| Departmentof Bioinformatics and Biostatistics | |
| University Institute of Oncology | |
| Sheffield Experimental Cancer Medicine Centre | |
| Congressionally Directed Medical Research Programs | |
| Fondation Institut Universitaire de Cardiologie et de Pneumologie de Québec | |
| Fonds de Recherche du Québec-Santé | |
| Study of Lung Cancer Epidemiology in North Trent | |
| Instytut Medycyny Pracy im. prof. J. Nofera | |
| Canada Research Chair in Pharmacogenomics | |
| National Institute for Health Research | |
| Overlæge Johan Boserup og Lise Boserups Legat | |
| Sheffield Hospitals Charity | |
| Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre | |
| National Institutes of Health (NIH) | |
| University of Texas Anderson Cancer Center | |
| Weston Park Hospital Cancer Charity | |
| Centre for Addiction and Mental Health Foundation | |
| IUOPA | |
| U.S. Department of Defense | |
| Université Laval | |
| Princess Margaret Cancer Foundation | |
| National Childhood Cancer Registry – National Cancer Institute | P30CA023108, P30CA071789, P30CA016672, P30CA177558, R01CA092824, UM1CA167462, K07CA172294, P50CA119997, R01CA063464, P50CA070907, U19CA148127, UM1CA164973, P20CA090578, R01CA111703, U01CA209414, P01CA033619, U19CA203654, P30CA008748, R01CA176568, R01CA151989, P30CA076292, R01CA074386 |
| Canadian Institutes of Health Research | MOP - 123369, FDN-154294 |
| National Center for Advancing Translational Sciences (NCATS) | UL1TR000117, UL1TR000445 |
| Wellcome Trust | WT202849/Z/16/Z, 202849 |
| Vanderbilt Digestive Diseases Research Center, Vanderbilt University Medical Center | UL1TR000445, 1S10RR025141-01 |
| Cancer Prevention and Research Institute of Texas | RP130502 |
| Roy Castle Lung Cancer Foundation | CA092824, CA074386, CA090578, CA033619 |
| National Human Genome Research Institute | U01HG004798 |
| Union for International Cancer Control | FIS-PI03-0365, FIS-01/310, FIS-07-BI060604 |
| Herlev Hospital | P50 CA070907, R01 CA176568, P20RR018787 |
| James and Esther King Florida Biomedical Research Program | 09KN-15, P30CA76292, P50 CA119997 |
| Division of Cancer Prevention, National Cancer Institute | RR170048 |
| National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences | P20GM103534 |
| National Center for Research Resources | P20RR018787, S10RR025141 |
| Army Medical Research and Materiel Command | P30 CA177558, 10153006, UL1TR000117, W81XWH-11-1-0781 |
| Hospital Universitario Central de Asturias- Oviedo and Instituto de Investigación Biosanitaria del Principado de Asturias | FICYT IB09-133, FICYT PB02-67 |
| Universidad de Oviedo | R01 CA151989, UM1 CA167462, UO1-CA6367307, U01 CA167462 |
| U.S. National Library of Medicine | R56LM012371 |
| Canadian Cancer Society Research Institute | 020214 |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General
- General Physics and Astronomy
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