| Literature DB >> 25320178 |
Yi-Ping Fu1, Indu Kohaar1, Lee E Moore2, Petra Lenz3, Jonine D Figueroa2, Wei Tang1, Patricia Porter-Gill1, Nilanjan Chatterjee2, Alexandra Scott-Johnson1, Montserrat Garcia-Closas4, Brian Muchmore1, Dalsu Baris2, Ashley Paquin1, Kris Ylaya5, Molly Schwenn6, Andrea B Apolo7, Margaret R Karagas8, McAnthony Tarway1, Alison Johnson9, Adam Mumy1, Alan Schned8, Liliana Guedez10, Michael A Jones11, Masatoshi Kida12, G M Monawar Hosain13, Nuria Malats14, Manolis Kogevinas15, Adonina Tardon16, Consol Serra17, Alfredo Carrato18, Reina Garcia-Closas19, Josep Lloreta20, Xifeng Wu21, Mark Purdue2, Gerald L Andriole22, Robert L Grubb22, Amanda Black2, Maria T Landi2, Neil E Caporaso2, Paolo Vineis23, Afshan Siddiq24, H Bas Bueno-de-Mesquita25, Dimitrios Trichopoulos26, Börje Ljungberg27, Gianluca Severi28, Elisabete Weiderpass29, Vittorio Krogh30, Miren Dorronsoro31, Ruth C Travis32, Anne Tjønneland33, Paul Brennan34, Jenny Chang-Claude35, Elio Riboli24, Jennifer Prescott36, Constance Chen37, Immaculata De Vivo36, Edward Govannucci38, David Hunter37, Peter Kraft37, Sara Lindstrom37, Susan M Gapstur39, Eric J Jacobs39, W Ryan Diver39, Demetrius Albanes2, Stephanie J Weinstein2, Jarmo Virtamo40, Charles Kooperberg41, Chancellor Hohensee41, Rebecca J Rodabough41, Victoria K Cortessis42, David V Conti43, Manuela Gago-Dominguez44, Mariana C Stern43, Malcolm C Pike45, David Van Den Berg43, Jian-Min Yuan46, Christopher A Haiman43, Olivier Cussenot47, Geraldine Cancel-Tassin48, Morgan Roupret49, Eva Comperat49, Stefano Porru50, Angela Carta50, Sofia Pavanello51, Cecilia Arici50, Giuseppe Mastrangelo51, H Barton Grossman52, Zhaoming Wang53, Xiang Deng53, Charles C Chung53, Amy Hutchinson53, Laurie Burdette53, William Wheeler54, Joseph Fraumeni2, Stephen J Chanock2, Stephen M Hewitt5, Debra T Silverman2, Nathaniel Rothman2, Ludmila Prokunina-Olsson55.
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. ©2014 American Association for Cancer Research.Entities:
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Year: 2014 PMID： 25320178 PMCID： PMC4203382 DOI： 10.1158/0008-5472.CAN-14-1531
Source DB: PubMed Journal: Cancer Res ISSN： 0008-5472 Impact factor: 12.701