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Carcinogenesis. 2015 Nov;36(11):1314-26. doi: 10.1093/carcin/bgv128. Epub 2015 Sep 10.

Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia.

Author information

1
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.
2
Department of Community and Family Medicine, Center for Genomic Medicine, Geisel School of Medicine, Dartmouth College, Lebanon, NH 03766, USA.
3
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada.
4
Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH8 9YL, UK.
5
Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
6
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
7
Departments of Environmental Health and Epidemiology, Harvard University School of Public Health, Boston, MA 02115, USA.
8
Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, 37073 Göttingen, Germany.
9
Division of Health Sciences, Cancer Center and College of Medicine, Mayo Clinic, Rochester, NY 55905, USA.
10
Epidemiology Research Program, American Cancer Society, Epidemiology and Surveillance Research, Atlanta, GA 30301, USA.
11
Section of Genetics, International Agency for Research on Cancer, 69372 Lyon, France.
12
Population Sciences, Tisch Cancer Center and Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
13
Institute of Carcinogenesis, Russian N.N.Blokhin Cancer Research Centre, 115478 Moscow, Russia.
14
Department of Epidemiology, Institute of Occupational Medicine, 91348 Lodz, Poland.
15
Department of Epidemiology and Cancer Prevention, The M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw 02781, Poland.
16
National Institute of Environmental Health, Budapest 1097, Hungary.
17
Department of Health Risk Assessment, Regional Authority of Public Health, Banská Bystrica 97556, Slovak Republic.
18
National Institute of Public Health, Bucharest 050463, Romania.
19
Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University in Prague, 128 00 Prague 2, Czech Republic.
20
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno 65653, Czech Republic.
21
Department of Preventive Medicine, Palacky University, Olomouc 77515, Czech Republic.
22
Department of Cancer Research and Molecular Medicine, Faculty of Medicine.
23
Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine and.
24
Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim 7489, Norway.
25
Department of Community Medicine, University of Tromso, Tromso N-9037, Norway.
26
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
27
McGill University and Genome Québec Innovation Centre, Montréal, Quebec, Canada.
28
Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
29
Department of Biomedicine, University of Bergen, Bergen 5009, Norway.
30
Institute of Molecular and Cell Biology, Estonian Biocentre, Genotyping Core Facility, Tartu 51010, Estonia.
31
Department of Oncology, Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
32
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
33
Department of Genetics, U.T. M.D. Anderson Cancer Center, Houston, TX 77030, USA.
34
Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
35
Department of Preventive Medicine, Kyushu University Graduate School of Medicine, Fukuoka City 819-0395, Japan.
36
Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
37
Department of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Chikusa-ku Nagoya 464-0021, Japan.
38
Division of Epigenomics and Cancer Risk Factors, DKFZ, 69121 Heidelberg, Germany, Division of Epigenomics and Cancer Risk Factors, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), 69121 Heidelberg, Germany.
39
Unit of Environmental Epidemiology, Helmholtz Zentrum Munchen, 85764 Neuherberg, Germany.
40
Division of Epigenomics and Cancer Risk Factors, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), 69121 Heidelberg, Germany, Translational Research Unit and.
41
Division of Epigenomics and Cancer Risk Factors, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung Research (DZL), 69121 Heidelberg, Germany, Department of Thoracic Surgery, Thoraxklinik am Universitätsklinikum Heidelberg, 69117 Heidelberg, Germany.
42
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.
43
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
44
Medical Oncology and Haematology, Department of Medicine, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada.
45
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.
46
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
47
Keck School of Medicine, University of South California, Los Angeles, CA 90089-0911, USA and.
48
Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
49
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada, rayjean.hung@lunenfeld.ca.

Abstract

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.

PMID:
26363033
PMCID:
PMC4635669
DOI:
10.1093/carcin/bgv128
[Indexed for MEDLINE]
Free PMC Article

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