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Cancer Res. 2014 Oct 15;74(20):5808-18. doi: 10.1158/0008-5472.CAN-14-1531.

The 19q12 bladder cancer GWAS signal: association with cyclin E function and aggressive disease.

Author information

1
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
2
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
3
Clinical Research Directorate/Clinical Monitoring Research Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
4
Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom.
5
Laboratory of Pathology, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
6
Maine Cancer Registry, Augusta, Maine.
7
Genitourinary Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
8
Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
9
Vermont Cancer Registry, Burlington, Vermont.
10
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
11
Department of Pathology and Laboratory Medicine, Maine Medical Center, Portland, Maine.
12
Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont.
13
New Hampshire State Cancer Registry, Concord, New Hampshire.
14
Spanish National Cancer Research Centre, Madrid, Spain.
15
Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. National School of Public Health, Athens, Greece. CIBER Epidemiologia y Salud Pública (CIBERESP), Barcelona, Spain.
16
CIBER Epidemiologia y Salud Pública (CIBERESP), Barcelona, Spain. Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
17
CIBER Epidemiologia y Salud Pública (CIBERESP), Barcelona, Spain. Universitat Pompeu Fabra, Barcelona, Spain.
18
Ramón y Cajal Hospital, Madrid, Spain.
19
Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain.
20
Hospital del Mar-IMIM, Univesitat Pompeu Fabra, Barcelona, Spain.
21
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
22
Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri.
23
School of Public Health, Imperial College London, London, United Kingdom. Human Genetics Foundation (HuGeF), Torino, Italy.
24
School of Public Health, Imperial College London, London, United Kingdom.
25
National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, the Netherlands. Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom. Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
26
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts. Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. Hellenic Health Foundation, Athens, Greece.
27
Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
28
Human Genetics Foundation (HuGeF), Torino, Italy. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia. Centre for Epidemiology and Biostatistics, University of Melbourne, Australia.
29
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. Department of Research, Cancer Registry of Norway, Oslo, Norway. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Samfundet Folkhälsan, Helsinki, Finland.
30
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
31
Public Health Division of Gipuzkoa, Basque Regional Health Department and Ciberesp-Biodonostia, San Sebastian, Spain.
32
Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
33
Danish Cancer Society Research Center, Copenhagen, Denmark.
34
International Agency for Research on Cancer, Lyon, France.
35
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
36
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
37
Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
38
Department of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
39
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia.
40
National Institute for Health and Welfare, Helsinki, Finland.
41
Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington.
42
Department of Obstetrics and Gynecology, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. Department of Preventive Medicine, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
43
Department of Preventive Medicine, Keck School of Medicine of USC, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
44
Genomic Medicine Group, Galician Foundation of Genomic Medicine, Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saude (SERGAS), Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.
45
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York.
46
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
47
AP-HP, Hopital Tenon, GHU-Est, Department of Urology, Paris, France. Centre de Recherche sur les Pathologies Prostatiques, Paris, France. UPMC Univ Paris 06, ONCOTYPE-URO, Paris, France.
48
Centre de Recherche sur les Pathologies Prostatiques, Paris, France. UPMC Univ Paris 06, ONCOTYPE-URO, Paris, France.
49
Centre de Recherche sur les Pathologies Prostatiques, Paris, France. UPMC Univ Paris 06, ONCOTYPE-URO, Paris, France. AP-HP, Hopital Pitie-Salpetriere, GHU-Est, Departments of Urology and Pathology, Paris, France.
50
Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy.
51
Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padua, Italy.
52
Department of Urology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.
53
Cancer Genomics Research Laboratory, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
54
Information Management Services, Rockville, Maryland.
55
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. prokuninal@mail.nih.gov.

Abstract

A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P(trend) = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.

PMID:
25320178
PMCID:
PMC4203382
DOI:
10.1158/0008-5472.CAN-14-1531
[Indexed for MEDLINE]
Free PMC Article

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