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Function and Aggressive Disease The 19 q 12 Bladder Cancer GWAS Signal : Association with Cyclin E Updated

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 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 OR1⁄4 1.18 [95% confidence interval (CI), 1.09–1.27, P 1⁄4 4.67 10 ] versus OR 1⁄4 1.01 (95% CI, 0.93–1.10, P 1⁄4 0.79) for nonaggressive disease, with P 1⁄4 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P 1⁄4 0.013) and, independently, with each rs7257330-A risk allele (Ptrend 1⁄4 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. Cancer Res; 74(20); 5808–18. 2014 AACR. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Clinical Research Directorate/Clinical Monitoring Research Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland. Division of Genetics and Epidemiology, Institute of Cancer Research, London, United Kingdom. Laboratory of Pathology, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Maine Cancer Registry, Augusta, Maine. Genitourinary Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Vermont Cancer Registry, Burlington, Vermont. Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda,Maryland. Department of Pathology and LaboratoryMedicine, Maine Medical Center, Portland, Maine. Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont. New Hampshire State Cancer Registry, Concord, New Hampshire. Spanish National Cancer Research Centre, Madrid, Spain. 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 P ublica (CIBERESP), Barcelona, Spain. Instituto Universitario de Cancer Research Cancer Res; 74(20) October 15, 2014 5808 on October 30, 2014. © 2014 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from