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 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; 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

doi:10.1038/s41467-020-15905-6

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 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, 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

Pharmaceutical Sciences

Dartmouth College
Memorial Sloan-Kettering Cancer Center
National Institutes of Health
Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval
Baylor College of Medicine
University of Toronto
International Agency for Research on Cancer
Harvard University
Massachusetts General Hospital
University of Copenhagen
University of Hawai'i at Mānoa
University of Göttingen
Vanderbilt University
Case Western Reserve University
University of Oviedo
Clalit Health Services
Fred Hutchinson Cancer Research Center
Dartmouth Medical School Norris Cotton Cancer Center
University of Liverpool
Radboud University Nijmegen
National Institute of Occupational Health
Provincial Health Services Authority
Moffitt Cancer Center
IRCCS Fondazione Ca'Granda – Ospedale Maggiore Policlinico - Milano
University of Milan
University Health Network
University of Southern California
Sejong University
Lund University
Imperial College London
Helenic Health Foundation
“Civic - M.P. Arezzo” Hospital
Swedish Medical Group
University of Sheffield
Helmholtz Zentrum München - German Research Center for Environmental Health
Heidelberg University
Translational Lung Research Center Heidelberg (TLRC-H)
University of Salzburg
Umeå University
University of Kentucky
Institute of Pneumology “Marius Nasta”
Charles University
Palacký University Olomouc
University of Belgrade
Maria Sklodowska-Curie Institute of Oncology
Russian N.N. Blokhin Cancer Research Centre
International Organization for Cancer Prevention and Research
National Institute of Tuberculosis and Lung Diseases
Nofer Institute of Occupational Medicine
University of Bergen
University of Pittsburgh
The Institute of Cancer Research
American Cancer Society
Merck
The University of British Columbia Centre for Heart Lung Innovation
University of Groningen
University of Leicester
University Hospitals of Leicester NHS Trust
University of Texas MD Anderson Cancer Center
German Cancer Research Center
Dan L. Duncan Cancer Center

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

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.

Original language	English
Article number	2220
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15905-6
State	Published - Dec 1 2020

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Ji, X., Mukherjee, S., Landi, M. T., Bosse, Y., Joubert, P., Zhu, D., Gorlov, I., Xiao, X., Han, Y., Gorlova, O., Hung, R. J., Brhane, Y., Carreras-Torres, R., Christiani, D. C., Caporaso, N., Johansson, M., Liu, G., Bojesen, S. E., Le Marchand, L., ... Amos, C. I. (2020). Protein-altering germline mutations implicate novel genes related to lung cancer development. Nature Communications, 11(1), Article 2220. https://doi.org/10.1038/s41467-020-15905-6

@article{f4aa589f53334301a93464004abe304e,

title = "Protein-altering germline mutations implicate novel genes related to lung cancer development",

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 {\texttimes} 10−15) and replication (adjusted OR = 2.93, P = 2.22 {\texttimes} 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 {\texttimes} 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.",

author = "Xuemei Ji and Semanti Mukherjee and Landi, \{Maria Teresa\} and Yohan Bosse and Philippe Joubert and Dakai Zhu and Ivan Gorlov and Xiangjun Xiao and Younghun Han and Olga Gorlova and Hung, \{Rayjean J.\} and Yonathan Brhane and Robert Carreras-Torres and Christiani, \{David C.\} and Neil Caporaso and Mattias Johansson and Geoffrey Liu and Bojesen, \{Stig E.\} and \{Le Marchand\}, Loic and Demetrios Albanes and Heike Bickeb{\"o}ller and Aldrich, \{Melinda C.\} and Bush, \{William S.\} and Adonina Tardon and Gad Rennert and Chu Chen and Jinyoung Byun and Dragnev, \{Konstantin H.\} and Field, \{John K.\} and Kiemeney, \{Lambertus Fa\} and Philip Lazarus and Shan Zienolddiny and Stephen Lam and Schabath, \{Matthew B.\} and Andrew, \{Angeline S.\} and Bertazzi, \{Pier A.\} and Pesatori, \{Angela C.\} and Nancy Diao and Li Su and Lei Song and Ruyang Zhang and Natasha Leighl and Johansen, \{Jakob S.\} and Anders Mellemgaard and Walid Saliba and Christopher Haiman and Lynne Wilkens and Ana Fernandez-Somoano and Guillermo Fernandez-Tardon and Heijden, \{Erik H.F.M.van der\} and Kim, \{Jin Hee\} and Davies, \{Michael P.A.\} and Marcus, \{Michael W.\} and Hans Brunnstr{\"o}m and Jonas Manjer and Olle Melander and Muller, \{David C.\} and Kim Overvad and Antonia Trichopoulou and Rosario Tumino and Goodman, \{Gary E.\} and Angela Cox and Fiona Taylor and Penella Woll and Erich Wichmann and Thomas Muley and Angela Risch and Albert Rosenberger and Kjell Grankvist and Mikael Johansson and Frances Shepherd and Tsao, \{Ming Sound\} and Arnold, \{Susanne M.\} and Haura, \{Eric B.\} and Ciprian Bolca and Ivana Holcatova and Vladimir Janout and Milica Kontic and Jolanta Lissowska and Anush Mukeria and Simona Ognjanovic and Orlowski, \{Tadeusz M.\} and Ghislaine Scelo and Beata Swiatkowska and David Zaridze and Per Bakke and Vidar Skaug and Butler, \{Lesley M.\} and Kenneth Offit and Preethi Srinivasan and Chaitanya Bandlamudi and Hellmann, \{Matthew D.\} and Solit, \{David B.\} and Robson, \{Mark E.\} and Rudin, \{Charles M.\} and Stadler, \{Zsofia K.\} and Taylor, \{Barry S.\} and Berger, \{Michael F.\} and Richard Houlston and John McLaughlin and Victoria Stevens and Nickle, \{David C.\} and Ma{\textquoteright}en Obeidat and Wim Timens and Artigas, \{Mar{\'i}a Soler\} and Sanjay Shete and Hermann Brenner and Stephen Chanock and Paul Brennan and McKay, \{James D.\} and Amos, \{Christopher I.\}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

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doi = "10.1038/s41467-020-15905-6",

language = "English",

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issn = "2041-1723",

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Ji, X, Mukherjee, S, Landi, MT, Bosse, Y, Joubert, P, Zhu, D, Gorlov, I, Xiao, X, Han, Y, Gorlova, O, Hung, RJ, Brhane, Y, Carreras-Torres, R, Christiani, DC, Caporaso, N, Johansson, M, Liu, G, Bojesen, SE, Le Marchand, L, Albanes, D, Bickeböller, H, Aldrich, MC, Bush, WS, Tardon, A, Rennert, G, Chen, C, Byun, J, Dragnev, KH, Field, JK, Kiemeney, LF, Lazarus, P, Zienolddiny, S, Lam, S, Schabath, MB, Andrew, AS, Bertazzi, PA, Pesatori, AC, Diao, N, Su, L, Song, L, Zhang, R, Leighl, N, Johansen, JS, Mellemgaard, A, Saliba, W, Haiman, C, Wilkens, L, Fernandez-Somoano, A, Fernandez-Tardon, G, Heijden, EHFMVD, Kim, JH, Davies, MPA, Marcus, MW, Brunnström, H, Manjer, J, Melander, O, Muller, DC, Overvad, K, Trichopoulou, A, Tumino, R, Goodman, GE, Cox, A, Taylor, F, Woll, P, Wichmann, E, Muley, T, Risch, A, Rosenberger, A, Grankvist, K, Johansson, M, Shepherd, F, Tsao, MS, Arnold, SM, Haura, EB, Bolca, C, Holcatova, I, Janout, V, Kontic, M, Lissowska, J, Mukeria, A, Ognjanovic, S, Orlowski, TM, Scelo, G, Swiatkowska, B, Zaridze, D, Bakke, P, Skaug, V, Butler, LM, Offit, K, Srinivasan, P, Bandlamudi, C, Hellmann, MD, Solit, DB, Robson, ME, Rudin, CM, Stadler, ZK, Taylor, BS, Berger, MF, Houlston, R, McLaughlin, J, Stevens, V, Nickle, DC, Obeidat, M, Timens, W, Artigas, MS, Shete, S, Brenner, H, Chanock, S, Brennan, P, McKay, JD & Amos, CI 2020, 'Protein-altering germline mutations implicate novel genes related to lung cancer development', Nature Communications, vol. 11, no. 1, 2220. https://doi.org/10.1038/s41467-020-15905-6

TY - JOUR

T1 - Protein-altering germline mutations implicate novel genes related to lung cancer development

AU - Ji, Xuemei

AU - Mukherjee, Semanti

AU - Landi, Maria Teresa

AU - Bosse, Yohan

AU - Joubert, Philippe

AU - Zhu, Dakai

AU - Gorlov, Ivan

AU - Xiao, Xiangjun

AU - Han, Younghun

AU - Gorlova, Olga

AU - Hung, Rayjean J.

AU - Brhane, Yonathan

AU - Carreras-Torres, Robert

AU - Christiani, David C.

AU - Caporaso, Neil

AU - Johansson, Mattias

AU - Liu, Geoffrey

AU - Bojesen, Stig E.

AU - Le Marchand, Loic

AU - Albanes, Demetrios

AU - Bickeböller, Heike

AU - Aldrich, Melinda C.

AU - Bush, William S.

AU - Tardon, Adonina

AU - Rennert, Gad

AU - Chen, Chu

AU - Byun, Jinyoung

AU - Dragnev, Konstantin H.

AU - Field, John K.

AU - Kiemeney, Lambertus Fa

AU - Lazarus, Philip

AU - Zienolddiny, Shan

AU - Lam, Stephen

AU - Schabath, Matthew B.

AU - Andrew, Angeline S.

AU - Bertazzi, Pier A.

AU - Pesatori, Angela C.

AU - Diao, Nancy

AU - Su, Li

AU - Song, Lei

AU - Zhang, Ruyang

AU - Leighl, Natasha

AU - Johansen, Jakob S.

AU - Mellemgaard, Anders

AU - Saliba, Walid

AU - Haiman, Christopher

AU - Wilkens, Lynne

AU - Fernandez-Somoano, Ana

AU - Fernandez-Tardon, Guillermo

AU - Heijden, Erik H.F.M.van der

AU - Kim, Jin Hee

AU - Davies, Michael P.A.

AU - Marcus, Michael W.

AU - Brunnström, Hans

AU - Manjer, Jonas

AU - Melander, Olle

AU - Muller, David C.

AU - Overvad, Kim

AU - Trichopoulou, Antonia

AU - Tumino, Rosario

AU - Goodman, Gary E.

AU - Cox, Angela

AU - Taylor, Fiona

AU - Woll, Penella

AU - Wichmann, Erich

AU - Muley, Thomas

AU - Risch, Angela

AU - Rosenberger, Albert

AU - Grankvist, Kjell

AU - Johansson, Mikael

AU - Shepherd, Frances

AU - Tsao, Ming Sound

AU - Arnold, Susanne M.

AU - Haura, Eric B.

AU - Bolca, Ciprian

AU - Holcatova, Ivana

AU - Janout, Vladimir

AU - Kontic, Milica

AU - Lissowska, Jolanta

AU - Mukeria, Anush

AU - Ognjanovic, Simona

AU - Orlowski, Tadeusz M.

AU - Scelo, Ghislaine

AU - Swiatkowska, Beata

AU - Zaridze, David

AU - Bakke, Per

AU - Skaug, Vidar

AU - Butler, Lesley M.

AU - Offit, Kenneth

AU - Srinivasan, Preethi

AU - Bandlamudi, Chaitanya

AU - Hellmann, Matthew D.

AU - Solit, David B.

AU - Robson, Mark E.

AU - Rudin, Charles M.

AU - Stadler, Zsofia K.

AU - Taylor, Barry S.

AU - Berger, Michael F.

AU - Houlston, Richard

AU - McLaughlin, John

AU - Stevens, Victoria

AU - Nickle, David C.

AU - Obeidat, Ma’en

AU - Timens, Wim

AU - Artigas, María Soler

AU - Shete, Sanjay

AU - Brenner, Hermann

AU - Chanock, Stephen

AU - Brennan, Paul

AU - McKay, James D.

AU - Amos, Christopher I.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85084474621

U2 - 10.1038/s41467-020-15905-6

DO - 10.1038/s41467-020-15905-6

M3 - Article

C2 - 32393777

AN - SCOPUS:85084474621

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2220

ER -

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

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