Περίληψη:
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 x 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. (C) 2014 AACR.
Συγγραφείς:
Fu, Yi-Ping
Kohaar, Indu
Moore, Lee E.
Lenz, Petra and
Figueroa, Jonine D.
Tang, Wei
Porter-Gill, Patricia and
Chatterjee, Nilanjan
Scott-Johnson, Alexandra
Garcia-Closas,
Montserrat
Muchmore, Brian
Baris, Dalsu
Paquin, Ashley and
Ylaya, Kris
Schwenn, Molly
Apolo, Andrea B.
Karagas,
Margaret R.
Tarway, McAnthony
Johnson, Alison
Mumy, Adam and
Schned, Alan
Guedez, Liliana
Jones, Michael A.
Kida,
Masatoshi
Hosain, G. M. Monawar
Malats, Nuria
Kogevinas,
Manolis
Tardon, Adonina
Serra, Consol
Carrato, Alfredo and
Garcia-Closas, Reina
Lloreta, Josep
Wu, Xifeng
Purdue, Mark
and Andriole, Jr., Gerald L.
Grubb, III, Robert L.
Black, Amanda
and Landi, Maria T.
Caporaso, Neil E.
Vineis, Paolo
Siddiq,
Afshan
Bueno-de-Mesquita, H. Bas
Trichopoulos, Dimitrios and
Ljungberg, Boerje
Severi, Gianluca
Weiderpass, Elisabete and
Krogh, Vittorio
Dorronsoro, Miren
Travis, Ruth C. and
Tjonneland, Anne
Brennan, Paul
Chang-Claude, Jenny
Riboli,
Elio
Prescott, Jennifer
Chen, Constance
De Vivo, Immaculata
and Govannucci, Edward
Hunter, David
Kraft, Peter
Lindstrom,
Sara
Gapstur, Susan M.
Jacobs, Eric J.
Diver, W. Ryan and
Albanes, Demetrius
Weinstein, Stephanie J.
Virtamo, Jarmo and
Kooperberg, Charles
Hohensee, Chancellor
Rodabough, Rebecca J.
and 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 and
Burdette, Laurie
Wheeler, William
Fraumeni, Jr., Joseph and
Chanock, Stephen J.
Hewitt, Stephen M.
Silverman, Debra T. and
Rothman, Nathaniel
Prokunina-Olsson, Ludmila
