The 19q12 Bladder Cancer GWAS Signal: Association with Cyclin E Function and Aggressive Disease
Authors: Fu Yi-Ping , Kohaar Indu , Moore Lee E. , Lenz Petra , Figueroa Jonine D. , Tang Wei , Porter-Gill Patricia , Chatterjee Nilanjan , Scott-Johnson Alexandra , Garcia-Closas Montserrat , Muchmore Brian , Baris Dalsu , Paquin Ashley , Ylaya Kris , Schwenn Molly , Apolo Andrea B. , Karagas Margaret R. , Tarway McAnthony , Johnson Alison , Mumy Adam , Schned Alan , Guedez Liliana , Jones Michael A. , Kida Masatoshi , Hosain GM Monawar , Malats Nuria , Kogevinas Manolis , Tardon Adonina , Serra Consol , Carrato Alfredo , Garcia-Closas Reina , Lloreta Josep , Wu Xifeng , Purdue Mark , Andriole Gerald L. , Grubb Robert L. , Black Amanda , Landi Maria T. , Caporaso Neil E. , Vineis Paolo , Siddiq Afshan , Bueno-de-Mesquita H. Bas , Trichopoulos Dimitrios , Ljungberg Börje , Severi Gianluca , Weiderpass Elisabete , Krogh Vittorio , Dorronsoro Miren , Travis Ruth C. , Tjønneland Anne , Brennan Paul , Chang-Claude Jenny , Riboli Elio , Prescott Jennifer , Chen Constance , De Vivo Immaculata , Govannucci Edward , Hunter David , Kraft Peter , Lindstrom Sara , Gapstur Susan M. , Jacobs Eric J. , Diver W. Ryan , Albanes Demetrius , Weinstein Stephanie J. , Virtamo Jarmo , Kooperberg Charles , Hohensee Chancellor , Rodabough Rebecca J. , Cortessis Victoria K. , Conti David V. , Gago-Dominguez Manuela , Stern Mariana C. , Pike Malcolm C. , Van Den Berg David , Yuan Jian-Min , Haiman Christopher A. , Cussenot Olivier , Cancel-Tassin Geraldine , Roupret Morgan , Comperat Eva , Porru Stefano , Carta Angela , Pavanello Sofia , Arici Cecilia , Mastrangelo Giuseppe , Grossman H. Barton , Wang Zhaoming , Deng Xiang , Chung Charles C. , Hutchinson Amy , Burdette Laurie , Wheeler William , Fraumeni Joseph , Chanock Stephen J. , Hewitt Stephen M. , Silverman Debra T. , Rothman Nathaniel , Prokunina-Olsson Ludmila 
Published: October 2014

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 r2 ≥ 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 (Ptrend = 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.