Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10-6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: Rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10-11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10-10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer. Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.
Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of european ancestry / Figueroa, J. D.; Middlebrooks, C. D.; Banday, A. R.; Ye, Y.; Garcia-Closas, M.; Chatterjee, N.; Koutros, S.; Kiemeney, L. A.; Rafnar, T.; Bishop, T.; Furberg, H.; Matullo, G.; Golka, K.; Gago-Dominguez, M.; Taylor, J. A.; Fletcher, T.; Siddiq, A.; Cortessis, V. K.; Kooperberg, C.; Cussenot, O.; Benhamou, S.; Prescott, J.; Porru, S.; Dinney, C. P.; Malats, N.; Baris, D.; Purdue, M. P.; Jacobs, E. J.; Albanes, D.; Wang, Z.; Chung, C. C.; Vermeulen, S. H.; Aben, K. K.; Galesloot, T. E.; Thorleifsson, G.; Sulem, P.; Stefansson, K.; Kiltie, A. E.; Harland, M.; Teo, M.; Offit, K.; Vijai, J.; Bajorin, D.; Kopp, R.; Fiorito, G.; Guarrera, S.; Sacerdote, C.; Selinski, S.; Hengstler, J. G.; Gerullis, H.; Ovsiannikov, D.; Blaszkewicz, M.; Castelao, J. E.; Calaza, M.; Martinez, M. E.; Cordeiro, P.; Xu, Z.; Panduri, V.; Kumar, R.; Gurzau, E.; Koppova, K.; Bueno-De-Mesquita, H. B.; Ljungberg, B.; Clavel-Chapelon, F.; Weiderpass, E.; Krogh, V.; Dorronsoro, M.; Travis, R. C.; Tjonneland, A.; Brennan, P.; Chang-Claude, J.; Riboli, E.; Conti, D.; Stern, M. C.; Pike, M. C.; Van Den Berg, D.; Yuan, J. -M.; Hohensee, C.; Jeppson, R. P.; Cancel-Tassin, G.; Roupret, M.; Comperat, E.; Turman, C.; De Vivo, I.; Giovannucci, E.; Hunter, D. J.; Kraft, P.; Lindstrom, S.; Carta, A.; Pavanello, S.; Arici, C.; Mastrangelo, G.; Kamat, A. M.; Zhang, L.; Gong, Y.; Pu, X.; Hutchinson, A.; Burdett, L.; Wheeler, W. A.; Karagas, M. R.; Johnson, A.; Schned, A.; Monawar Hosain, G. M.; Schwenn, M.; Kogevinas, M.; Tardon, A.; Serra, C.; Carrato, A.; Garcia-Closas, R.; Lloreta, J.; Andriole, G.; Robert, G.; Black, A.; Diver, W. R.; Gapstur, S. M.; Weinstein, S.; Virtamo, J.; Haiman, C. A.; Landi, M. T.; Caporaso, N. E.; Joseph, F.; Vineis, P.; Wu, X.; Chanock, S. J.; Silverman, D. T.; Prokunina-Olsson, L.; Rothman, N.. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 25:6(2015), pp. 1203-1214. [10.1093/hmg/ddv492]
Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of european ancestry
Fiorito G.;
2015-01-01
Abstract
Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10-6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: Rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10-11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10-10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer. Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
