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


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

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Journal Title

Cancer research

MeSH Headings

Case-Control Studies, Chromosomes, Human, Pair 19, Cyclin E, Gene Expression, Gene Frequency, Genome-Wide Association Study, Haplotypes, HeLa Cells, Humans, Oncogene Proteins, Polymorphism, Single Nucleotide, Urinary Bladder, Urinary Bladder Neoplasms




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.

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