Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10(-8)) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10(-7)) and MTMR2 at 11q21 (rs10501831, P = 3.1×10(-6)) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10(-7)) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10(-4) for KCNIP4, represented by rs9799795) and AC (P = 2.16×10(-4) for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.

Cancer Epidemiology Program University of Hawaii Cancer Center Honolulu HI 96813 USA

Center for Genomic Medicine Graduate School of Medicine Kyoto University Kyoto 606 8501 Japan

Department of Biomedicine University of Bergen Bergen 5009 Norway

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno 65653 Czech Republic

Department of Cancer Research and Molecular Medicine Faculty of Medicine

Department of Community and Family Medicine Center for Genomic Medicine Geisel School of Medicine Dartmouth College Lebanon NH 03766 USA

Department of Community Medicine University of Tromso Tromso N 9037 Norway

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY 10065 USA

Department of Epidemiology and Biostatistics School of Public Health Nanjing Medical University Nanjing 210029 China

Department of Epidemiology and Cancer Prevention The M Sklodowska Curie Memorial Cancer Center and Institute of Oncology Warsaw 02781 Poland

Department of Epidemiology and Prevention Aichi Cancer Center Research Institute Chikusa ku Nagoya 464 0021 Japan

Department of Epidemiology Harvard School of Public Health Boston MA 02115 USA Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA 02115 USA

Department of Epidemiology Institute of Occupational Medicine 91348 Lodz Poland

Department of Epidemiology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

Department of Genetic Epidemiology University Medical Center Georg August University Göttingen 37073 Göttingen Germany

Department of Genetics U T M D Anderson Cancer Center Houston TX 77030 USA

Department of Health and Human Services Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD 20892 USA

Department of Health Risk Assessment Regional Authority of Public Health Banská Bystrica 97556 Slovak Republic

Department of Laboratory Medicine Children's and Women's Health Faculty of Medicine and

Department of Oncology Cambridge Biomedical Research Centre Cambridge CB2 0QQ UK

Department of Preventive Medicine Kyushu University Graduate School of Medicine Fukuoka City 819 0395 Japan

Department of Preventive Medicine Palacky University Olomouc 77515 Czech Republic

Department of Public Health and General Practice Faculty of Medicine Norwegian University of Science and Technology Trondheim 7489 Norway

Departments of Environmental Health and Epidemiology Harvard University School of Public Health Boston MA 02115 USA

Division of Epigenomics and Cancer Risk Factors DKFZ 69121 Heidelberg Germany Division of Epigenomics and Cancer Risk Factors Translational Lung Research Center Heidelberg 69121 Heidelberg Germany

Division of Epigenomics and Cancer Risk Factors Translational Lung Research Center Heidelberg 69121 Heidelberg Germany Department of Thoracic Surgery Thoraxklinik am Universitätsklinikum Heidelberg 69117 Heidelberg Germany

Division of Epigenomics and Cancer Risk Factors Translational Lung Research Center Heidelberg 69121 Heidelberg Germany Translational Research Unit and

Division of Genetics and Epidemiology The Institute of Cancer Research Sutton Surrey SM2 5NG UK

Division of Health Sciences Cancer Center and College of Medicine Mayo Clinic Rochester NY 55905 USA

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA 98109 USA

Duncan Cancer Center Baylor College of Medicine Houston TX 77030 USA

Epidemiology Research Program American Cancer Society Epidemiology and Surveillance Research Atlanta GA 30301 USA

Institute of Carcinogenesis Russian N N Blokhin Cancer Research Centre 115478 Moscow Russia

Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh EH8 9YL UK

Institute of Hygiene and Epidemiology 1st Faculty of Medicine Charles University Prague 128 00 Prague 2 Czech Republic

Institute of Molecular and Cell Biology Estonian Biocentre Genotyping Core Facility Tartu 51010 Estonia

Institute of Molecular and Cell Biology University of Tartu Tartu 51010 Estonia

Keck School of Medicine University of South California Los Angeles CA 90089 0911 USA and

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario M5T 3L9 Canada

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario M5T 3L9 Canada Section of Genetics International Agency for Research on Cancer 69372 Lyon France Department of Cancer Epidemiology and Prevention Research Cancer Control Alberta Alberta Health Services Calgary Alberta T2T 5C7 Canada

McGill University and Genome Québec Innovation Centre Montréal Quebec Canada

Medical Oncology and Haematology Department of Medicine Princess Margaret Hospital Toronto Ontario M5G 2M9 Canada

National Institute of Environmental Health Budapest 1097 Hungary

National Institute of Public Health Bucharest 050463 Romania

Population Sciences Tisch Cancer Center and Institute for Translational Epidemiology Icahn School of Medicine at Mount Sinai New York NY 10029 USA

Roy Castle Lung Cancer Research Programme The University of Liverpool Cancer Research Centre Department of Molecular and Clinical Cancer Medicine Institute of Translational Medicine The University of Liverpool Liverpool L69 3BX UK

Section of Genetics International Agency for Research on Cancer 69372 Lyon France

Unit of Environmental Epidemiology Helmholtz Zentrum Munchen 85764 Neuherberg Germany

Zobrazit více v PubMed

Jemal A., et al. (2011) Global cancer statistics. CA. Cancer J. Clin., 61, 69–90. PubMed

Brennan P., et al. (2011) Genetics of lung-cancer susceptibility. Lancet. Oncol., 12, 399–408. PubMed

Pietanza M.C., et al. (2012) Bringing the genomic landscape of small-cell lung cancer into focus. Nat. Genet., 44, 1074–1075. PubMed

Sun S., et al. (2007) Lung cancer in never smokers—a different disease. Nat. Rev. Cancer, 7, 778–790. PubMed

Thorgeirsson T.E., et al. (2008) A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature, 452, 638–642. PubMed PMC

Amos C.I., et al. (2008) Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat. Genet., 40, 616–622. PubMed PMC

Hung R.J., et al. (2008) A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature, 452, 633–637. PubMed

McKay J.D., et al. (2008) Lung cancer susceptibility locus at 5p15.33. Nat. Genet., 40, 1404–1406. PubMed PMC

Landi M.T., et al. (2009) A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am. J. Hum. Genet., 85, 679–691. PubMed PMC

Wang Y., et al. (2014) Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat. Genet., 46, 736–741. PubMed PMC

Wang Y., et al. (2008) Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat. Genet., 40, 1407–1409. PubMed PMC

Shi J., et al. (2012) Inherited variation at chromosome 12p13.33, including RAD52, influences the risk of squamous cell lung carcinoma. Cancer Discov., 2, 131–139. PubMed PMC

Hung R.J., et al. (2007) Inherited predisposition of lung cancer: a hierarchical modeling approach to DNA repair and cell cycle control pathways. Cancer Epidemiol. Biomark. Prev., 16, 2736–2744. PubMed

Truong T., et al. (2010) International Lung Cancer Consortium: coordinated association study of 10 potential lung cancer susceptibility variants. Carcinogenesis, 31, 625–633. PubMed PMC

Hu Z., et al. (2011) A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese. Nat. Genet., 43, 792–796. PubMed

Timofeeva M.N., et al. (2012) Influence of common genetic variation on lung cancer risk: meta-analysis of 14,900 cases and 29,485 controls. Hum. Mol. Genet., 21, 4980–4995. PubMed PMC

Sun L., et al. (2006) Stratified false discovery control for large-scale hypothesis testing with application to genome-wide association studies. Genet. Epidemiol., 30, 519–530. PubMed

Wakefield J. (2007) A Bayesian measure of the probability of false discovery in genetic epidemiology studies. Am. J. Hum. Genet., 81, 208–227. PubMed PMC

Chen G.K., et al. (2007) Enriching the analysis of genomewide association studies with hierarchical modeling. Am. J. Hum. Genet., 81, 397–404. PubMed PMC

Field J.K., et al. (2005) The Liverpool Lung Project research protocol. Int. J. Oncol., 27, 1633–1645. PubMed

Rafnar T., et al. (2011) Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk. Cancer Res., 71, 1356–1361. PubMed PMC

Sauter W., et al. (2008) Matrix metalloproteinase 1 (MMP1) is associated with early-onset lung cancer. Cancer Epidemiol. Biomark. Prev., 17, 1127–1135. PubMed

Brenner D.R., et al. (2010) Lung cancer risk in never-smokers: a population-based case-control study of epidemiologic risk factors. BMC Cancer, 10, 285. PubMed PMC

Su L., et al. (2006) Genotypes and haplotypes of matrix metalloproteinase 1, 3 and 12 genes and the risk of lung cancer. Carcinogenesis, 27, 1024–1029. PubMed

Landi M.T., et al. (2008) Environment And Genetics in Lung cancer Etiology (EAGLE) study: an integrative population-based case-control study of lung cancer. BMC Public Health, 8, 203. PubMed PMC

The ATBC Cancer Prevention Study Group. (1994) The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. Ann. Epidemiol., 4, 1–10. PubMed

Hayes R.B., et al. (2005) Methods for etiologic and early marker investigations in the PLCO trial. Mutat. Res., 592, 147–154. PubMed

Calle E.E., et al. (2002) The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics. Cancer, 94, 2490–2501. PubMed

Brennan P., et al. (2006) High cumulative risk of lung cancer death among smokers and nonsmokers in Central and Eastern Europe. Am. J. Epidemiol., 164, 1233–1241. PubMed

Orlow I., et al. (2008) DNA damage and repair capacity in patients with lung cancer: prediction of multiple primary tumors. J. Clin. Oncol., 26, 3560–3566. PubMed PMC

Li Y., et al. (2010) Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. Lancet. Oncol., 11, 321–330. PubMed PMC

Ito H., et al. (2012) Association between a genome-wide association study-identified locus and the risk of lung cancer in Japanese population. J. Thorac. Oncol., 7, 790–798. PubMed

Hosking L., et al. (2004) Detection of genotyping errors by Hardy-Weinberg equilibrium testing. Eur. J. Hum. Genet., 12, 395–399. PubMed

Higgins J.P., et al. (2003) Measuring inconsistency in meta-analyses. BMJ, 327, 557–560. PubMed PMC

Purcell S., et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet., 81, 559–575. PubMed PMC

Pruim R.J., et al. (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics, 26, 2336–2337. PubMed PMC

Wakefield J. (2007) A Bayesian measure of the probability of false discovery in genetic epidemiology studies. Am. J. Hum. Genet., 81, 208–207. PubMed PMC

Illumina. (2006) Technical Bulletin: Whole-Genome Genotyping with the Sentrix HumanHap550 Genotyping BeadChip and the Infinium II Assay. Illumina, Inc, San Diego, CA.

Siepel A., et al. (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res., 15, 1034–1050. PubMed PMC

Ng P.C., et al. (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res., 31, 3812–3814. PubMed PMC

Johnson A.D., et al. (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics, 24, 2938–2939. PubMed PMC

Storey J.D., et al. (2003) Statistical significance for genomewide studies. Proc. Natl Acad. Sci. USA, 100, 9440–9445. PubMed PMC

Hindorff L.A., et al. (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA, 106, 9362–9367. PubMed PMC

Wakefield J. (2008) Reporting and interpretation in genome-wide association studies. Int. J. Epidemiol., 37, 641–653. PubMed

Wakefield J. (2009) Bayes factors for genome-wide association studies: comparison with P-values. Genet. Epidemiol., 33, 79–86. PubMed

Brenner D.R., et al. (2013) Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls. Hum. Genet., 132, 579–589. PubMed PMC

Greenland S. (1993) Methods for epidemiologic analyses of multiple exposures: a review and comparative study of maximum-likelihood, preliminary-testing, and empirical-Bayes regression. Stat. Med., 12, 717–736. PubMed

Mägi R., et al. (2010) GWAMA: software for genome-wide association meta-analysis. BMC Bioinform., 11, 288. PubMed PMC

Imielinski M., et al. (2012) Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell, 150, 1107–1120. PubMed PMC

Hammerman P.S., et al. (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature, 489, 519–525. PubMed PMC

Govindan R., et al. (2012) Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell, 150, 1121–1134. PubMed PMC

Pruunsild P., et al. (2005) Structure, alternative splicing, and expression of the human and mouse KCNIP gene family. Genomics, 86, 581–593. PubMed

Bonne A., et al. (2007) Mapping of constitutional translocation breakpoints in renal cell cancer patients: identification of KCNIP4 as a candidate gene. Cancer Genet. Cytogenet., 179, 11–18. PubMed

Rossner P., Jr, et al. (2006) Relationship between urinary 15-F2t-isoprostane and 8-oxodeoxyguanosine levels and breast cancer risk. Cancer Epidemiol. Biomark. Prev., 15, 639–644. PubMed

Himes B.E., et al. (2013) Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene. PLoS One, 8, e56179. PubMed PMC

Rosenberger A., et al. (2012) Asthma and lung cancer risk: a systematic investigation by the International Lung Cancer Consortium. Carcinogenesis, 33, 587–597. PubMed PMC

Tashiro K., et al. (2009) GAREM, a novel adaptor protein for growth factor receptor-bound protein 2, contributes to cellular transformation through the activation of extracellular signal-regulated kinase signaling. J. Biol. Chem., 284, 20206–20214. PubMed PMC

Zollner S., et al. (2007) Overcoming the winner’s curse: estimating penetrance parameters from case-control data. Am. J. Hum. Genet., 80, 605–615. PubMed PMC

Boyle A.P., et al. (2012) Annotation of functional variation in personal genomes using RegulomeDB. Genome Res., 22, 1790–1797. PubMed PMC

Ward L.D., et al. (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res., 40, D930–D934. PubMed PMC

Schaub M.A., et al. (2012) Linking disease associations with regulatory information in the human genome. Genome Res., 22, 1748–1759. PubMed PMC

Hung R.J., et al. (2008) International Lung Cancer Consortium: pooled analysis of sequence variants in DNA repair and cell cycle pathways. Cancer Epidemiol. Biomark. Prev., 17, 3081–3089. PubMed PMC

Maurano M.T., et al. (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science, 337, 1190–1195. PubMed PMC

GTEx Consortium. (2013) The Genotype-Tissue Expression (GTEx) project. Nat. Genet., 45, 580–585. PubMed PMC

Cancer Genome Atlas Research Network. (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature, 489, 519–525. PubMed PMC

Pan W., et al. (2015) Testing for polygenic effects in genome-wide association studies. Genet. Epidemiol., 39, 306–316. PubMed PMC

Knight J., et al. (2011) Using functional annotation for the empirical determination of Bayes Factors for genome-wide association study analysis. PLoS One, 6, e14808. PubMed PMC

Johansson M., et al. (2012) Using prior information from the medical literature in GWAS of oral cancer identifies novel susceptibility variant on chromosome 4—the AdAPT method. PLoS One, 7, e36888. PubMed PMC

Sun L., et al. (2012) Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nat. Genet., 44, 562–569. PubMed PMC

Multi-Omics Analysis Reveals a HIF Network and Hub Gene EPAS1 Associated with Lung Adenocarcinoma