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 AlbanesHeike 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

34 Citations (Scopus)

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
Pages (from-to)	2220
ISSN	2041-1722
DOIs	https://doi.org/10.1038/s41467-020-15905-6
Publication status	Published - 11 May 2020

Keywords

Adenocarcinoma/genetics
Aged
Alleles
Ataxia Telangiectasia Mutated Proteins/genetics
Databases, Genetic
European Continental Ancestry Group/genetics
Female
Genetic Predisposition to Disease
Genotyping Techniques
Germ-Line Mutation
Heterozygote
Humans
Jews/genetics
Lung Neoplasms/genetics
Male
Middle Aged
Mutation, Missense
Odds Ratio
Oligonucleotide Array Sequence Analysis
Pedigree
RNA-Seq
Risk Factors

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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), 2220. Article 2220. https://doi.org/10.1038/s41467-020-15905-6

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, M-S, 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, pp. 2220. https://doi.org/10.1038/s41467-020-15905-6

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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 × 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.",

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year = "2020",

month = may,

day = "11",

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

language = "English",

volume = "11",

pages = "2220",

journal = "Nature Communications",

issn = "2041-1722",

publisher = "Nature Publishing Group",

number = "1",

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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 - 2020/5/11

Y1 - 2020/5/11

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.

KW - Adenocarcinoma/genetics

KW - Aged

KW - Alleles

KW - Ataxia Telangiectasia Mutated Proteins/genetics

KW - Databases, Genetic

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Genotyping Techniques

KW - Germ-Line Mutation

KW - Heterozygote

KW - Humans

KW - Jews/genetics

KW - Lung Neoplasms/genetics

KW - Male

KW - Middle Aged

KW - Mutation, Missense

KW - Odds Ratio

KW - Oligonucleotide Array Sequence Analysis

KW - Pedigree

KW - RNA-Seq

KW - Risk Factors

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

U2 - 10.1038/s41467-020-15905-6

DO - 10.1038/s41467-020-15905-6

M3 - Journal article

C2 - 32393777

SN - 2041-1722

VL - 11

SP - 2220

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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Keywords

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