Publication Title

Nat Commun

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-Torres
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 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, Swedish Medical Group, Seattle, WAFollow
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

Document Type

Article

Publication Date

5-11-2020

Keywords

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

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.

Clinical Institute

Cancer

Specialty

Oncology

Included in

Oncology Commons

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