Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls

Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21–6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10−16), 6p21 (P = 2.3 × 10−14) and 15q25 (P = 2.2 × 10−63). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16INK4A/p14ARF/CDKN2B/p15INK4B/ANRIL; rs1333040, P = 3.0 × 10−7) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10−8). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer.

Yang Zhao | Andres Metspalu | Paul Brennan | Wei Chen | Christopher I. Amos | Kari Stefansson | Dakai Zhu | Hongbing Shen | Neil E. Caporaso | Maria Teresa Landi | David C. Christiani | John K. Field | Gudmar Thorleifsson | Jolanta Lissowska | Angela Risch | Thomas Muley | Gary Goodman | Vladimir Janout | Hans E. Krokan | Thorunn Rafnar | Xifeng Wu | John McLaughlin | Heike Bickeböller | Rayjean J. Hung | K. Stefánsson | M. Thun | Hongbing Shen | M. Spitz | H. Dienemann | G. Thorleifsson | Xifeng Wu | L. Vatten | A. Metspalu | C. Amos | T. Eisen | W. Chen | R. Houlston | D. Albanes | D. Brenner | M. Lathrop | D. Christiani | T. Rafnar | V. Gaborieau | J. Lissowska | T. Vooder | P. Rudnai | A. Risch | I. Njølstad | H. Bickeböller | T. Muley | E. Fabianova | M. Nelis | F. Skorpen | D. Zaridze | V. Janout | V. Bencko | D. Mates | R. Hung | Yang Zhao | J. Dai | S. Narod | T. Liloglou | G. Goodman | J. McLaughlin | P. Brennan | M. Landi | N. Caporaso | M. Timofeeva | H. Wichmann | S. Benhamou | J. McKay | Younghun Han | Yufei Wang | H. Krokan | Kristjan Välk | Chu Chen | J. Field | O. Raji | A. Rosenberger | J. Gosney | Dakai Zhu | Juncheng Dai | Hendrik Dienemann | Mark Lathrop | Demetrius Albanes | Richard Houlston | Steven A. Narod | Younghun Han | Mala Pande | Timothy Eisen | Michael Thun | Inger Njølstad | Simone Benhamou | Eleonora Fabianova | Chu Chen | Lenka Foretova | Mari Nelis | David Zaridze | Peter Rudnai | Dana Mates | Vladimir Bencko | Tõnu Vooder | Kristjan Välk | Albert Rosenberger | Margaret Spitz | Lars Vatten | Triantafillos Liloglou | Valerie Gaborieau | Yufei Wang | Maria N. Timofeeva | Frank Skorpen | James D. McKay | Neonilia Szeszenia-Dabrowska | Maiken Elvestad Gabrielsen | Darren Brenner | H.-Erich Wichmann | Olaide Raji | Ying Chen | John Gosney | Mala Pande | M. Gabrielsen | N. szeszenia-Dabrowska | Ying Chen | L. Foretova | J. Mckay | E. Fabiánová | J. McLaughlin

[1]  Per Gustavsson,et al.  Cigarette smoking and lung cancer—relative risk estimates for the major histological types from a pooled analysis of case–control studies , 2012, International journal of cancer.

[2]  J. Marchini,et al.  Fast and accurate genotype imputation in genome-wide association studies through pre-phasing , 2012, Nature Genetics.

[3]  A. Ashworth,et al.  The potential of exploiting DNA-repair defects for optimizing lung cancer treatment , 2012, Nature Reviews Clinical Oncology.

[4]  Jianxin Shi,et al.  Inherited variation at chromosome 12p13.33, including RAD52, influences the risk of squamous cell lung carcinoma. , 2012, Cancer discovery.

[5]  T. Ogihara,et al.  Genome-wide association study of coronary artery disease in the Japanese , 2011, European Journal of Human Genetics.

[6]  宇野 智子.  A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese , 2012 .

[7]  L. Tanoue,et al.  Lung cancer: epidemiology, etiology, and prevention. , 2011, Clinics in chest medicine.

[8]  Jostein Holmen m.fl.  The Nord-Trøndelag Health Study 1995-97 (HUNT 2) , 2011 .

[9]  Qiong Chen,et al.  Silencing of the human TERT gene by RNAi inhibits A549 lung adenocarcinoma cell growth in vitro and in vivo. , 2011, Oncology reports.

[10]  R. Scott,et al.  Smoking Related Cancers and Loci at Chromosomes 15q25, 5p15, 6p22.1 and 6p21.33 in the Polish Population , 2011, PloS one.

[11]  Wen Tan,et al.  A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese , 2011, Nature Genetics.

[12]  Mark I McCarthy,et al.  Genomic inflation factors under polygenic inheritance , 2011, European Journal of Human Genetics.

[13]  N. Mehta.  Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. , 2011, Circulation. Cardiovascular genetics.

[14]  M. Brown,et al.  Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1 , 2011, Nature Genetics.

[15]  P. McKeigue,et al.  Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from Starr County, Texas , 2011, Diabetologia.

[16]  M. Kitagawa,et al.  Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15INK4B tumor suppressor gene , 2011, Oncogene.

[17]  Paolo Boffetta,et al.  Genetics of lung-cancer susceptibility. , 2011, The Lancet. Oncology.

[18]  D. Gudbjartsson,et al.  Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk. , 2011, Cancer research.

[19]  I. Bièche,et al.  ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  Ibrahim Emam,et al.  ArrayExpress update—an archive of microarray and high-throughput sequencing-based functional genomics experiments , 2010, Nucleic Acids Res..

[21]  Yang Xue-ning.  International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma , 2011 .

[22]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[23]  Andres Metspalu,et al.  Gene Expression Profiles of Non-Small Cell Lung Cancer: Survival Prediction and New Biomarkers , 2011, Oncology.

[24]  Yusuke Nakamura,et al.  A genome-wide association study reveals susceptibility variants for non-small cell lung cancer in the Korean population. , 2010, Human molecular genetics.

[25]  G. Abecasis,et al.  MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes , 2010, Genetic epidemiology.

[26]  John P. Rice,et al.  Multiple cholinergic nicotinic receptor genes affect nicotine dependence risk in African and European Americans , 2010, Genes, brain, and behavior.

[27]  Yusuke Nakamura,et al.  Variation in TP63 is associated with lung adenocarcinoma susceptibility in Japanese and Korean populations , 2010, Nature Genetics.

[28]  R. Nagai,et al.  Genome-Wide Association Study of Coronary Artery Disease , 2010, International journal of hypertension.

[29]  Hubert Vesselle,et al.  DNA hypermethylation of tumors from non-small cell lung cancer (NSCLC) patients is associated with gender and histologic type. , 2010, Lung cancer.

[30]  Yusuke Nakamura,et al.  A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese , 2010, Nature Genetics.

[31]  William Wheeler,et al.  Multiple Independent Loci at Chromosome 15q25.1 Affect Smoking Quantity: a Meta-Analysis and Comparison with Lung Cancer and COPD , 2010, PLoS genetics.

[32]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[33]  Paul Brennan,et al.  Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. , 2010, Journal of the National Cancer Institute.

[34]  Ayellet V. Segrè,et al.  Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis , 2010, Nature Genetics.

[35]  Y. Nakanishi,et al.  Cigarette smoking, TP53 Arg72Pro, TP53BP1 Asp353Glu and the risk of lung cancer in a Japanese population. , 2010, Oncology reports.

[36]  Tariq Ahmad,et al.  Meta-analysis and imputation refines the association of 15q25 with smoking quantity , 2010, Nature Genetics.

[37]  M. Thun,et al.  International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants. , 2010, Carcinogenesis.

[38]  Bernard Keavney,et al.  Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression , 2010, PLoS genetics.

[39]  J. Subramanian,et al.  Distinctive Characteristics of Non-small Cell Lung Cancer (NSCLC) in the Young: A Surveillance, Epidemiology, and End Results (SEER) Analysis , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[40]  Ying Wang,et al.  A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. , 2009, American journal of human genetics.

[41]  A. Gabrielsen,et al.  Relationship between CAD Risk Genotype in the Chromosome 9p21 Locus and Gene Expression. Identification of Eight New ANRIL Splice Variants , 2009, PloS one.

[42]  J. Parker,et al.  Functional Analysis of the Chromosome 9p21.3 Coronary Artery Disease Risk Locus , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[43]  M. Spitz,et al.  Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study. , 2009, Cancer research.

[44]  R. Houlston,et al.  The TERT-CLPTM1L lung cancer susceptibility variant associates with higher DNA adduct formation in the lung. , 2009, Carcinogenesis.

[45]  Melissa Bondy,et al.  Genome-wide association study identifies five susceptibility loci for glioma , 2009, Nature Genetics.

[46]  Alexander R. Pico,et al.  Variants in the CDKN2B and RTEL1 regions are associated with high grade glioma susceptibility , 2009, Nature Genetics.

[47]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[48]  R. Mägi,et al.  Genetic Structure of Europeans: A View from the North–East , 2009, PloS one.

[49]  F. Takeuchi,et al.  Confirmation of Multiple Risk Loci and Genetic Impacts by a Genome-Wide Association Study of Type 2 Diabetes in the Japanese Population , 2009, Diabetes.

[50]  D. Glavač,et al.  The expression of COX-2, hTERT, MDM2, LATS2 and S100A2 in different types of non-small cell lung cancer (NSCLC) , 2009, Cellular & Molecular Biology Letters.

[51]  G. Abecasis,et al.  Genotype imputation. , 2009, Annual review of genomics and human genetics.

[52]  Christopher I Amos,et al.  Common 5p15.33 and 6p21.33 variants influence lung cancer risk , 2008, Nature Genetics.

[53]  Murim Choi,et al.  Susceptibility loci for intracranial aneurysm in European and Japanese populations , 2008, Nature Genetics.

[54]  Simon Heath,et al.  Lung cancer susceptibility locus at 5p15.33 , 2008, Nature Genetics.

[55]  M. Daly,et al.  Genetic Mapping in Human Disease , 2008, Science.

[56]  M. Lathrop,et al.  Variants in DNA double‐strand break repair and DNA damage‐response genes and susceptibility to lung and head and neck cancers , 2008, International journal of cancer.

[57]  S. Wacholder,et al.  Environment And Genetics in Lung cancer Etiology (EAGLE) study: An integrative population-based case-control study of lung cancer , 2008, BMC public health.

[58]  G. Mills,et al.  Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1 , 2008, Nature Genetics.

[59]  Florian Kronenberg,et al.  Matrix Metalloproteinase 1 (MMP1) Is Associated with Early-Onset Lung Cancer , 2008, Cancer Epidemiology Biomarkers & Prevention.

[60]  Daniel F. Gudbjartsson,et al.  A variant associated with nicotine dependence, lung cancer and peripheral arterial disease , 2008, Nature.

[61]  Paolo Vineis,et al.  A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25 , 2008, Nature.

[62]  R. Wozniak,et al.  Nup53 is required for nuclear envelope and nuclear pore complex assembly. , 2008, Molecular biology of the cell.

[63]  A. Jakubowska,et al.  Constitutional CHEK2 mutations are associated with a decreased risk of lung and laryngeal cancers. , 2008, Carcinogenesis.

[64]  A. Feinberg,et al.  Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA , 2008, Nature.

[65]  David C Christiani,et al.  Second hand smoke, age of exposure and lung cancer risk. , 2007, Lung cancer.

[66]  T. Eisen,et al.  Bmc Cancer Identification of Low Penetrance Alleles for Lung Cancer: the Genetic Lung Cancer Predisposition Study (gelcaps) , 2008 .

[67]  Florian Kronenberg,et al.  Do genetic factors protect for early onset lung cancer? A case control study before the age of 50 years , 2008, BMC Cancer.

[68]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[69]  R. Peto,et al.  Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers: case control study. , 2007, Human molecular genetics.

[70]  Yurii S. Aulchenko,et al.  BIOINFORMATICS APPLICATIONS NOTE doi:10.1093/bioinformatics/btm108 Genetics and population analysis GenABEL: an R library for genome-wide association analysis , 2022 .

[71]  T. Mak,et al.  HLA-B-associated transcript 3 (Bat3)/Scythe is essential for p300-mediated acetylation of p53. , 2007, Genes & development.

[72]  G. Peters,et al.  Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all , 2006, Nature Reviews Molecular Cell Biology.

[73]  J. Thierry-Mieg,et al.  AceView: a comprehensive cDNA-supported gene and transcripts annotation , 2006, Genome Biology.

[74]  T. Eisen,et al.  Variants in the GH-IGF axis confer susceptibility to lung cancer. , 2006, Genome research.

[75]  M. Spitz,et al.  An epidemiologic study of early onset lung cancer. , 2006, Lung cancer.

[76]  Xihong Lin,et al.  Genotypes and haplotypes of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer. , 2006, Carcinogenesis.

[77]  C. Power,et al.  Cohort profile: 1958 British birth cohort (National Child Development Study). , 2006, International journal of epidemiology.

[78]  Robert N Hoover,et al.  Methods for etiologic and early marker investigations in the PLCO trial. , 2005, Mutation research.

[79]  S. Duffy,et al.  The Liverpool Lung Project research protocol. , 2005, International journal of oncology.

[80]  F. Desmots,et al.  The Reaper-Binding Protein Scythe Modulates Apoptosis and Proliferation during Mammalian Development , 2005, Molecular and Cellular Biology.

[81]  D. Clayton,et al.  Population structure, differential bias and genomic control in a large-scale, case-control association study , 2005, Nature Genetics.

[82]  C. Gieger,et al.  KORA-gen - Resource for Population Genetics, Controls and a Broad Spectrum of Disease Phenotypes , 2005, Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany)).

[83]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[84]  L. Stovner,et al.  The Nord-Trøndelag Health Study , 2005 .

[85]  P. Brennan,et al.  Occupational Exposure to Vinyl Chloride, Acrylonitrile and Styrene and Lung Cancer Risk (Europe) , 2004, Cancer Causes & Control.

[86]  S. Gabriel,et al.  Assessing the impact of population stratification on genetic association studies , 2004, Nature Genetics.

[87]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[88]  M. Thun,et al.  The American Cancer Society Cancer Prevention Study II Nutrition Cohort , 2002, Cancer.

[89]  Arnulf Langhammer,et al.  The Nord-Trøndelag Health Study 1995-97 (HUNT 2): Objectives, contents, methods and participation , 2003 .

[90]  P. Dayer,et al.  Point: myeloperoxidase -463G --> a polymorphism and lung cancer risk. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[91]  W James Gauderman,et al.  Sample size requirements for matched case‐control studies of gene–environment interaction , 2002, Statistics in medicine.

[92]  M. Thun,et al.  The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics. , 2002, Cancer.

[93]  John Calvin Reed,et al.  Molecular chaperone targeting and regulation by BAG family proteins , 2001, Nature Cell Biology.

[94]  K. Khanna,et al.  DNA double-strand breaks: signaling, repair and the cancer connection , 2001, Nature Genetics.

[95]  L. Sobin,et al.  World Health Organization classification of tumors , 2000, Cancer.

[96]  P. Donnelly,et al.  Inference of population structure using multilocus genotype data. , 2000, Genetics.

[97]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[98]  J. Yokota,et al.  Association of CDKN2A (p16)/CDKN2B (p15) alterations and homozygous chromosome arm 9p deletions in human lung carcinoma , 1998, Genes, chromosomes & cancer.

[99]  J. Fletcher,et al.  Codeletion of p15 and p16 genes in primary non-small cell lung carcinoma. , 1995, Cancer research.

[100]  R. Ueda,et al.  In vivo occurrence of p16 (MTS1) and p15 (MTS2) alterations preferentially in non-small cell lung cancers. , 1995, Cancer research.

[101]  W. Clark,et al.  Germline p16 mutations in familial melanoma , 1994, Nature Genetics.

[102]  G. Omenn,et al.  The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers. , 1994, Cancer research.

[103]  The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. The ATBC Cancer Prevention Study Group. , 1994, Annals of epidemiology.