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

Xuemei Ji (), Semanti Mukherjee, Maria Teresa Landi, Yohan Bosse, Philippe Joubert, Dakai Zhu, Ivan Gorlov, Xiangjun Xiao, Younghun Han, Olga Gorlova, Rayjean J. Hung, Yonathan Brhane, Robert Carreras-Torres, David C. Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Chu Chen, Jinyoung Byun, Konstantin H. Dragnev, John K. Field, Lambertus FA. Kiemeney, Philip Lazarus, Shan Zienolddiny, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Pier A. Bertazzi, Angela C. Pesatori, Nancy Diao, Li Su, Lei Song, Ruyang Zhang, Natasha Leighl, Jakob S. Johansen, Anders Mellemgaard, Walid Saliba, Christopher Haiman, Lynne Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Erik H. F. M. van der Heijden, Jin Hee Kim, Michael P. A. Davies, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Gary E. Goodman, Angela Cox, Fiona Taylor, Penella Woll, Erich Wichmann, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances Shepherd, Ming-Sound Tsao, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Lesley M. Butler, Kenneth Offit, Preethi Srinivasan, Chaitanya Bandlamudi, Matthew D. Hellmann, David B. Solit, Mark E. Robson, Charles M. Rudin, Zsofia K. Stadler, Barry S. Taylor, Michael F. Berger, Richard Houlston, John McLaughlin, Victoria Stevens, David C. Nickle, Ma’en Obeidat, Wim Timens, María Soler Artigas, Sanjay Shete, Hermann Brenner, Stephen Chanock, Paul Brennan, James D. McKay and Christopher I. Amos ()
Additional contact information
Xuemei Ji: Geisel School of Medicine at Dartmouth
Semanti Mukherjee: Memorial Sloan Kettering Cancer Center
Maria Teresa Landi: National Institutes of Health
Yohan Bosse: Laval University
Philippe Joubert: Laval University
Dakai Zhu: Geisel School of Medicine at Dartmouth
Ivan Gorlov: Geisel School of Medicine at Dartmouth
Xiangjun Xiao: The Institute for Clinical and Translational Research, Baylor College of Medicine
Younghun Han: The Institute for Clinical and Translational Research, Baylor College of Medicine
Olga Gorlova: Geisel School of Medicine at Dartmouth
Rayjean J. Hung: Sinai Health System and University of Toronto
Yonathan Brhane: Sinai Health System and University of Toronto
Robert Carreras-Torres: International Agency for Research on Cancer, World Health Organization
David C. Christiani: Harvard T.H. Chan School of Public Health
Neil Caporaso: National Institutes of Health
Mattias Johansson: International Agency for Research on Cancer, World Health Organization
Geoffrey Liu: Sinai Health System and University of Toronto
Stig E. Bojesen: Copenhagen University Hospital
Loic Marchand: University of Hawaii Cancer Center
Demetrios Albanes: National Institutes of Health
Heike Bickeböller: University Medical Center, Georg-August-University Göttingen
Melinda C. Aldrich: Vanderbilt University Medical Center
William S. Bush: Case Western Reserve University
Adonina Tardon: IUOPA. University of Oviedo and CIBERESP, Faculty of Medicine, Campus del Cristo s/n
Gad Rennert: Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine
Chu Chen: Fred Hutchinson Cancer Research Center
Jinyoung Byun: The Institute for Clinical and Translational Research, Baylor College of Medicine
Konstantin H. Dragnev: The Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center
John K. Field: University of Liverpool
Lambertus FA. Kiemeney: Radboud University Medical Center, Radboud Institute for Health Sciences
Philip Lazarus: College of Pharmacy, Washington State University
Shan Zienolddiny: National Institute of Occupational Health
Stephen Lam: British Columbia Cancer Agency
Matthew B. Schabath: H. Lee Moffitt Cancer Center and Research Institute
Angeline S. Andrew: Geisel School of Medicine
Pier A. Bertazzi: IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico
Angela C. Pesatori: IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico
Nancy Diao: Harvard T.H. Chan School of Public Health
Li Su: Harvard T.H. Chan School of Public Health
Lei Song: National Institutes of Health
Ruyang Zhang: Harvard T.H. Chan School of Public Health
Natasha Leighl: University Health Network- The Princess Margaret Cancer Centre
Jakob S. Johansen: Herlev and Gentofte Hospital, Copenhagen University Hospital
Anders Mellemgaard: Herlev and Gentofte Hospital, Copenhagen University Hospital
Walid Saliba: Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine
Christopher Haiman: Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center
Lynne Wilkens: University of Hawaii Cancer Center
Ana Fernandez-Somoano: IUOPA. University of Oviedo and CIBERESP, Faculty of Medicine, Campus del Cristo s/n
Guillermo Fernandez-Tardon: IUOPA. University of Oviedo and CIBERESP, Faculty of Medicine, Campus del Cristo s/n
Erik H. F. M. van der Heijden: Radboud University Medical Center, Radboud Institute for Health Sciences
Jin Hee Kim: Sejong University
Michael P. A. Davies: University of Liverpool
Michael W. Marcus: University of Liverpool
Hans Brunnström: Lund University
Jonas Manjer: Lund University
Olle Melander: Lund University
David C. Muller: School of Public Health, St Mary’s Campus, Imperial College London
Kim Overvad: Lund University
Antonia Trichopoulou: Hellenic Health Foundation
Rosario Tumino: “Civic - M.P. Arezzo” Hospital
Gary E. Goodman: Fred Hutchinson Cancer Research Center
Angela Cox: University of Sheffield
Fiona Taylor: University of Sheffield
Penella Woll: University of Sheffield
Erich Wichmann: Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health
Thomas Muley: Thoraxklinik at University Hospital Heidelberg
Angela Risch: University of Salzburg and Cancer Cluster Salzburg
Albert Rosenberger: University Medical Center, Georg-August-University Göttingen
Kjell Grankvist: Umeå University
Mikael Johansson: Umeå University
Frances Shepherd: Princess Margaret Cancer Centre
Ming-Sound Tsao: Princess Margaret Cancer Centre
Susanne M. Arnold: University of Kentucky, Markey Cancer Center
Eric B. Haura: H. Lee Moffitt Cancer Center and Research Institute
Ciprian Bolca: Institute of Pneumology “Marius Nasta”
Ivana Holcatova: Charles University, 1st Faculty of Medicine
Vladimir Janout: Palacky University
Milica Kontic: University of Belgrade
Jolanta Lissowska: M. Sklodowska-Curie Institute – Oncology Center
Anush Mukeria: Russian N.N.Blokhin Cancer Research Centre
Simona Ognjanovic: International Organization for Cancer Prevention and Research
Tadeusz M. Orlowski: National Tuberculosis and Lung Diseases Research Institute
Ghislaine Scelo: International Agency for Research on Cancer, World Health Organization
Beata Swiatkowska: Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology
David Zaridze: Russian N.N.Blokhin Cancer Research Centre
Per Bakke: University of Bergen
Vidar Skaug: National Institute of Occupational Health
Lesley M. Butler: University of Pittsburgh Cancer Institute
Kenneth Offit: Memorial Sloan Kettering Cancer Center
Preethi Srinivasan: Memorial Sloan Kettering Cancer Center
Chaitanya Bandlamudi: Marie-Josée and Henry R. KravisCenter for Molecular Oncology, Memorial Sloan Kettering Cancer Center
Matthew D. Hellmann: Memorial Sloan Kettering Cancer Center
David B. Solit: Memorial Sloan Kettering Cancer Center
Mark E. Robson: Memorial Sloan Kettering Cancer Center
Charles M. Rudin: Memorial Sloan Kettering Cancer Center
Zsofia K. Stadler: Memorial Sloan Kettering Cancer Center
Barry S. Taylor: Marie-Josée and Henry R. KravisCenter for Molecular Oncology, Memorial Sloan Kettering Cancer Center
Michael F. Berger: Memorial Sloan Kettering Cancer Center
Richard Houlston: The Institute of Cancer Research
John McLaughlin: University of Toronto
Victoria Stevens: American Cancer Society, Inc.
David C. Nickle: Merck Research Laboratories, Genetics and Pharmacogenomics
Ma’en Obeidat: The University of British Columbia Centre for Heart Lung Innovation, St Paul’s Hospital
Wim Timens: University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, GRIAC research institute
María Soler Artigas: University of Leicester
Sanjay Shete: The University of Texas MD Anderson Cancer Center
Hermann Brenner: German Cancer Research Center (DKFZ)
Stephen Chanock: National Institutes of Health
Paul Brennan: International Agency for Research on Cancer, World Health Organization
James D. McKay: International Agency for Research on Cancer, World Health Organization
Christopher I. Amos: The Institute for Clinical and Translational Research, Baylor College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15905-6

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