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

• DOI: 10.1038/s41467-020-15905-6
• Publication Date: 2020-05-11T10:03:49Z
• Authors: 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-T...; David C. Christiani; Neil Caporaso; Mattias Johansson; Geoffrey Liu; Stig E. Bojesen; Loic Le Marchand; Demetrios Albanes; Heike Bickeböller; Melinda C. Aldrich; William S. Bush; Adonina Tardon; Gad Rennert; Chu Chen; Jinyoung Byun; Konstantin H. Dra...; John K. Field; Lambertus FA. Kie...; 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-Som...; Guillermo Fernand...; Erik H. F. M. van...; 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; Christopher I. Amos
• Keywords: Male; Heterozygote; Lung Neoplasms; Genotyping Techniques; Science; European Continental Ancestry Group; Mutation, Missense; 610; Radboud University Medical Center; Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences; Ataxia Telangiectasia Mutated Proteins; Adenocarcinoma; Article; Medical Genetics and Genomics; 618; Databases; 03 medical and health sciences; Genetic; Risk Factors; Adenocarcinoma; Aged; Alleles; Ataxia Telangiectasia Mutated Proteins; Databases, Genetic; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genotyping Techniques; Germ-Line Mutation; Heterozygote; Humans; Jews; Lung Neoplasms; Male; Middle Aged; Mutation, Missense; Odds Ratio; Oligonucleotide Array Sequence Analysis; Pedigree; RNA-Seq; Risk Factors; Databases, Genetic; Odds Ratio; Humans; Genetic Predisposition to Disease; RNA-Seq; Alleles; Germ-Line Mutation; Aged; Oligonucleotide Array Sequence Analysis; 0303 health sciences; Q; Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences; Middle Aged; Medicinsk genetik och genomik; Pedigree; 3. Good health; Jews; Mutation; Female; Missense; Pulmonary Diseases - Radboud University Medical Center; Health Evidence - Radboud University Medical Center

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