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

Fu, Y. P.; Kohaar, I.; Moore, L. E.; Lenz, P.; Figueroa, J. D.; Tang, W.; Porter-Gill, P.; Chatterjee, N.; Scott-Johnson, A.; Garcia-Closas, M.; Muchmore, B.; Baris, D.; Paquin, A.; Ylaya, K.; Schwenn, M.; Apolo, A. B.; Karagas, M. R.; Tarway, M.; Johnson, A.; Mumy, A.; Schned, A.; Guedez, L.; Jones, M. A.; Kida, M.; Hosain, G. M.; Malats, N.; Kogevinas, M.; Tardon, A.; Serra, C.; Carrato, A.; Garcia-Closas, R.; Lloreta, J.; Wu, X.; Purdue, M.; Andriole, G. L.; Grubb, R. L.; Black, A.; Landi, M. T.; Caporaso, N. E.; Vineis, P.; Siddiq, A.; Bueno-de-Mesquita, H. B.; Trichopoulos, D.; Ljungberg, B.; Severi, G.; Weiderpass, E.; Krogh, V.; Dorronsoro, M.; Travis, R. C.; Tjønneland, A.; Brennan, P.; Chang-Claude, J.; Riboli, E.; Prescott, J.; Chen, C.; De Vivo, I.; Govannucci, E.; Hunter, D.; Kraft, P.; Lindstrom, S.; Gapstur, S. M.; Jacobs, E. J.; Diver, W. R.; Albanes, D.; Weinstein, S. J.; Virtamo, J.; Kooperberg, C.; Hohensee, C.; Rodabough, R. J.; Cortessis, V. K.; Conti, D. V.; Gago Dominguez, Manuela; Stern, M. C.; Pike, M. C.; Van Den Berg, D.; Yuan, J. M.; Haiman, C. A.; Cussenot, O.; Cancel-Tassin, G.; Roupret, M.; Comperat, E.; Porru, S.; Carta, A.; Pavanello, S.; Arici, C.; Mastrangelo, G.; Grossman, H. B.; Wang, Z.; Deng, X.; Chung, C. C.; Hutchinson, A.; Burdette, L.; Wheeler, W.; Fraumeni, J.; Chanock, S. J.; Hewitt, S. M.; Silverman, D. T.; Rothman, N.; Prokunina-Olsson, L.
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Date issued
2014
Journal title
CANCER RESEARCH
Type of content
Artigo
MeSH
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
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 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.