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Hum Mol Genet. 2016 Mar 15;25(6):1203-14. doi: 10.1093/hmg/ddv492. Epub 2016 Jan 4.

Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry.

Figueroa JD1, Middlebrooks CD2, Banday AR2, Ye Y3, Garcia-Closas M4, Chatterjee N2, Koutros S2, Kiemeney LA5, Rafnar T6, Bishop T7, Furberg H8, Matullo G9, Golka K10, Gago-Dominguez M11, Taylor JA12, Fletcher T13, Siddiq A14, Cortessis VK15, Kooperberg C16, Cussenot O17, Benhamou S18, Prescott J19, Porru S20, Dinney CP21, Malats N22, Baris D2, Purdue MP2, Jacobs EJ23, Albanes D2, Wang Z24, Chung CC25, Vermeulen SH5, Aben KK5, Galesloot TE5, Thorleifsson G6, Sulem P6, Stefansson K26, Kiltie AE27, Harland M7, Teo M28, Offit K29, Vijai J29, Bajorin D30, Kopp R31, Fiorito G9, Guarrera S9, Sacerdote C32, Selinski S10, Hengstler JG10, Gerullis H33, Ovsiannikov D34, Blaszkewicz M10, Castelao JE35, Calaza M36, Martinez ME37, Cordeiro P38, Xu Z39, Panduri V12, Kumar R40, Gurzau E41, Koppova K42, Bueno-De-Mesquita HB43, Ljungberg B44, Clavel-Chapelon F45, Weiderpass E46, Krogh V47, Dorronsoro M48, Travis RC49, Tjønneland A50, Brennan P51, Chang-Claude J40, Riboli E14, Conti D52, Stern MC52, Pike MC7, Van Den Berg D52, Yuan JM53, Hohensee C16, Jeppson RP16, Cancel-Tassin G54, Roupret M55, Comperat E56, Turman C57, De Vivo I58, Giovannucci E59, Hunter DJ60, Kraft P61, Lindstrom S57, Carta A20, Pavanello S62, Arici C20, Mastrangelo G62, Kamat AM21, Zhang L3, Gong Y3, Pu X3, Hutchinson A24, Burdett L24, Wheeler WA63, Karagas MR64, Johnson A65, Schned A64, Monawar Hosain GM66, Schwenn M67, Kogevinas M68, Tardón A69, Serra C70, Carrato A71, García-Closas R72, Lloreta J73, Andriole G Jr74, Grubb R 3rd74, Black A2, Diver WR23, Gapstur SM23, Weinstein S2, Virtamo J75, Haiman CA76, Landi MT2, Caporaso NE2, Fraumeni JF Jr2, Vineis P77, Wu X3, Chanock SJ2, Silverman DT2, Prokunina-Olsson L2, Rothman N2.

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA, Usher Institute of Population Health Sciences and Informatics, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK, jonine.figueroa@ed.ac.uk.
2
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
3
Department of Epidemiology, MD Anderson Cancer Center, Houston, TX, USA.
4
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA, Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
5
Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
6
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
7
Section of Epidemiology and Biostatistics.
8
Department of Epidemiology and Biostatistics.
9
Department of Medical Sciences, University of Turin, Turin, Italy, Human Genetics Foundation, Turin, Italy.
10
Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany.
11
Genomic Medicine Group, Galician Foundation of Genomic Medicine, Servicio Galego de Saude (SERGAS), Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.
12
Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Research Triangle Park, NC, USA.
13
London School of Hygiene and Tropical Medicine, London, UK.
14
School of Public Health.
15
Department of Preventive Medicine, USC Keck School of Medicine, Department of Obstetrics and Gynecology, Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
16
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
17
Department of Urology, Tenon, Centre de Recherche sur les Pathologies Prostatiques, Paris, France, UPMC Univ Paris 06, GRC n°5, ONCOTYPE-URO, Paris, France.
18
Institut national de la sante et de la recherche medicale, U946, Foundation Jean Dausset Centre d'Etude du Polymorphisme Humain (CEPH), Paris, France, Centre National de la Receherche Scientifique, UMR8200, Institut Gustave-Roussy, Villejuif, France.
19
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, Department of Epidemiology.
20
Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.
21
Department of Urology, MD Anderson Cancer Center, Houston, TX, USA.
22
Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
23
Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
24
Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD, USA.
25
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA, Department of Urology, MD Anderson Cancer Center, Houston, TX, USA.
26
deCODE Genetics/Amgen, Inc., Reykjavik, Iceland, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
27
CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, UK.
28
Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS9 7TF, UK.
29
Department of Medicine.
30
Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine.
31
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
32
Cancer Epidemiology, CPO Piemonte, Turin, Italy.
33
University Hospital for Urology, Klinikum Oldenburg, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, Oldenburg, Germany, Department of Urology, Lukasklinik Neuss, Germany.
34
Department of Urology, St. Josefs Hospital, Dortmund-Hörde, Germany.
35
Oncology and Genetics Unit, Complejo Hospitalario, Instituto de Investigacion Biomedica (IBI) Orense-Pontevedra-Vigo, Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
36
Genomic Medicine Group, Galician Foundation of Genomic Medicine, Servicio Galego de Saude (SERGAS), Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, Galicia, Spain.
37
Department of Family Medicine and Public Health, Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
38
Department of Urology, Complejo Hospitalario, University of Santiago de Compostela, Servicio Galego de Saude (SERGAS), Santiago de Compostela, Spain.
39
Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS).
40
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg; University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
41
Environmental Health Center, Cluj, Romania.
42
State Health Institute, Banska Bystrica, Slovakia.
43
School of Public Health, Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands, Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
44
Department of Surgical and Perioperative Sciences, Urology and Andrology, Umea University, Umea, Sweden.
45
Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, Villejuif F-94805, France, Université Paris Sud, UMRS 1018, Villejuif F-94805, France, Institut Gustave Roussy, Villejuif F-94805, France.
46
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway, Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
47
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
48
Health Department, BioDonostia Research Institute, Basque Region, Spain, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
49
Cancer Epidemiology Unit, University of Oxford, Oxford, UK.
50
Danish Cancer Society Research Center, Copenhagen, Denmark.
51
International Agency for Research on Cancer (IARC), Lyon, France.
52
School of Public Health, Department of Obstetrics and Gynecology.
53
University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
54
Centre de Recherche sur les Pathologies Prostatiques, Paris, France, UPMC Univ Paris 06, GRC n°5, ONCOTYPE-URO, Paris, France.
55
Department of Urology, Pitié-Salpétrière, Centre de Recherche sur les Pathologies Prostatiques, Paris, France, UPMC Univ Paris 06, GRC n°5, ONCOTYPE-URO, Paris, France.
56
Department of Pathology, Pitié-Salpétrière, Assistance-Publique Hôpitaux de Paris (APHP), Paris, France, Centre de Recherche sur les Pathologies Prostatiques, Paris, France, UPMC Univ Paris 06, GRC n°5, ONCOTYPE-URO, Paris, France.
57
Department of Epidemiology.
58
Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
59
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, Department of Epidemiology, Department of Nutrition.
60
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, Department of Epidemiology, Department of Nutrition, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
61
Department of Epidemiology, Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA.
62
Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy.
63
Information Management Services, Silver Spring, MD, USA.
64
Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
65
Vermont Cancer Registry, Burlington, VT, USA.
66
New Hampshire State Cancer Registry, Concord, NH, USA.
67
Maine Cancer Registry, Augusta, ME, USA.
68
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain, Municipal Institute of Medical Research, (IMIM-Hospital del Mar), Barcelona, Spain, National School of Public Health, Athens, Greece.
69
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
70
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain, Municipal Institute of Medical Research, (IMIM-Hospital del Mar), Barcelona, Spain, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
71
Ramon y Cajal University Hospital, IRYCIS, Madrid, Spain.
72
Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain.
73
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
74
Division of Urologic Surgery, Washington University School of Medicine, Saint Louis, MO, USA and.
75
Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
76
Department of Obstetrics and Gynecology.
77
Human Genetics Foundation, Turin, Italy, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Abstract

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

PMID:
26732427
PMCID:
PMC4817084
DOI:
10.1093/hmg/ddv492
[Indexed for MEDLINE]
Free PMC Article

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