Protein-altering germline mutations implicate novel genes related to lung cancer development
Xuemei Ji, Semanti Mukherjee, Maria Teresa Landi, Yohan Bossé, Philippe Joubert, Dakai Zhu, Ivan P. Gorlov, Xiangjun Xiao, Younghun Han, Olga Y. Gorlova, Rayjean J. Hung, Yonathan Brhane, Robert Carreras‐Torres, David C. Christiani, Neil E. Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loı̈c Le Marchand, Demetrius Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardón, 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 Alberto Bertazzi, Angela Cecilia Pesatori, Nancy Diao, Li Su, Lei Song, Ruyang Zhang, Natasha B. Leighl, Jakob Sidenius Johansen, Anders Mellemgaard, Walid Saliba, Christopher A. Haiman, Lynne R. Wilkens, Ana Fernández‐Somoano, Guillermo Fernández‐Tardón, 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 J. Woll, Erich Wichmann, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances A. Shepherd, Ming‐Sound Tsao, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcátová, Vladimír Janout, Milica Kontić, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz Orłowski, Ghislaine Scélo, Beata Świątkowska, Давид Заридзе, 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 S. Houlston, John McLaughlin
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.