Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

doi:10.1038/ng.3892

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

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Abstract

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

Original language	English
Pages (from-to)	1126-1132
Number of pages	7
Journal	Nature Genetics
Volume	49
Issue number	7
DOIs	https://doi.org/10.1038/ng.3892
State	Published - Jul 1 2017

Bibliographical note

Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

Funding

Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by grants U19-CA148127 and CA148127S1. ILCCO data harmonization is supported by the Cancer Care Ontario Research Chair of Population Studies to R.J.H. and the Lunenfeld-Tanenbaum Research Institute, Sinai Health System. Additional funding information is provided in the Supplementary Note. The TRICL-ILCCO OncoArray was supported by in-kind genotyping by the Centre for Inherited Disease Research (26820120008i-0-26800068-1). IARC acknowledges and thanks V. Gaborieau, M. Foll, L. Fernandez-Cuesta, P. Chopard, T. Delhomme and A. Chabrier for their technical assistance in this project. The authors would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the lung eQTL data set at Laval University. The lung eQTL study at Laval University was supported by the Fondation de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, the Respiratory Health Network of the FRQS and the Canadian Institutes of Health Research (MOP-123369). Y. Bossé holds a Canada Research Chair in Genomics of Heart and Lung Diseases.

Funders	Funder number
International Lung Cancer Consortium	CA148127S1, U19-CA148127
Lunenfeld-Tanenbaum Research Institute
Sinai Health System (Toronto)	26820120008i-0-26800068-1
National Childhood Cancer Registry – National Cancer Institute	P30CA023108
National Childhood Cancer Registry – National Cancer Institute
Université Laval
Fondation Institut Universitaire de Cardiologie et de Pneumologie de Québec
Canadian Institutes of Health Research	MOP-123369
Canadian Institutes of Health Research
Fonds de Recherche du Québec-Santé

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

ASJC Scopus subject areas

Genetics

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10.1038/ng.3892

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title = "Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes",

abstract = "Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.",

author = "McKay, \{James D.\} and Hung, \{Rayjean J.\} and Younghun Han and Xuchen Zong and Robert Carreras-Torres and Christiani, \{David C.\} and Caporaso, \{Neil E.\} and Mattias Johansson and Xiangjun Xiao and Yafang Li and Jinyoung Byun and Alison Dunning and Pooley, \{Karen A.\} and Qian, \{David C.\} and Xuemei Ji and Geoffrey Liu and Timofeeva, \{Maria N.\} and Bojesen, \{Stig E.\} and Xifeng Wu and Marchand, \{Loic Le\} and Demetrios Albanes and Heike Bickeb{\"o}ller and Aldrich, \{Melinda C.\} and Bush, \{William S.\} and Adonina Tardon and Gad Rennert and Teare, \{M. Dawn\} and Field, \{John K.\} and Kiemeney, \{Lambertus A.\} and Philip Lazarus and Aage Haugen and Stephen Lam and Schabath, \{Matthew B.\} and Andrew, \{Angeline S.\} and Hongbing Shen and Hong, \{Yun Chul\} and Yuan, \{Jian Min\} and Bertazzi, \{Pier Alberto\} and Pesatori, \{Angela C.\} and Yuanqing Ye and Nancy Diao and Li Su and Ruyang Zhang and Yonathan Brhane and Natasha Leighl and Johansen, \{Jakob S.\} and Anders Mellemgaard and Walid Saliba and Haiman, \{Christopher A.\} and Arnold, \{Susanne M.\}",

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AB - Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

Abstract

Bibliographical note

Funding

UN SDGs

ASJC Scopus subject areas

Access to Document

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