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 (r2 = 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. Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Bibliographical noteFunding Information:
See Supplementary Material for funding details. The authors acknowledge the following: Marie Audouin, Cécile Gaffory, Valérie Ondet; Leslie Carroll (Information Management Services, Silver Spring, MD, USA); Gemma Castaño-Vinyals (Institut Municipal d’Investigació Mèdica, Barcelona, Spain); Francisco Fernández (Institut Municipal d’Investigació Mèdica, Barcelona, Spain); Anna McIntosh (Westat, Inc., Rockville, MD, USA); Robert Saal (Westat, Rockville, MD, USA); Francisco Real [Spanish National Cancer Research Centre (CNIO), Madrid, Spain]; Maria Sala (Institut Municipal d’Investigació Mèdica, Barcelona, Spain); Kirk Snyder (Information Management Services, Inc., Silver Spring, MD); Anne Taylor (Information Management Services, Inc., Silver Spring, MD); Montserrat Torà (Institut Municipal d’Investigació Mèdica, Barcelona, Spain); JaneWang (Information Management Services, Silver Spring, MD, USA). WHI Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller. Clinical Coordinating Center: Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg. Investigators and Academic Centers: (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/ Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/ Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. For a list of all the investigators who have contributed to WHI science, please visit: https://cleo.whi.org/researchers/SitePages/ Write%20a%20Paper.aspx. The Memorial Sloan Kettering investigators gratefully acknowledge the MSK Cancer Center Support Grant/Core Grant (P30 CA008748).