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, JD; Middlebrooks, CD; Banday, AR; Ye, Y; Garcia-Closas, M; Chatterjee, N; Koutros, S; Kiemeney, LA; Rafnar, T; Bishop, T; Furberg, H; Matullo, G; Golka, K; Gago-Dominguez, M; Taylor, JA; Fletcher, T; Siddiq, A; Cortessis, VK; Kooperberg, C; Cussenot, O; Benhamou, S; Prescott, J; Porru, S; Dinney, CP; Malats, N; Baris, D; Purdue, MP; Jacobs, EJ; Albanes, D; Wang, Z; Chung, CC; Vermeulen, SH; Aben, KK; Galesloot, TE; Thorleifsson, G; Sulem, P; Stefansson, K; Kiltie, AE; Harland, M; Teo, M; Offit, K; Vijai, J; Bajorin, D; Kopp, R; Fiorito, G; Guarrera, S; Sacerdote, C; Selinski, S; Hengstler, JG; Gerullis, H; Ovsiannikov, D; Blaszkewicz, M; Esteban Castelao, J; Calaza, M; Martinez, ME; Cordeiro, P; Xu, Z; Panduri, V; Kumar, R; Gurzau, E; Koppova, K; Bueno-de-Mesquita, HB; Ljungberg, B; Clavel-Chapelon, F; Weiderpass, E; Krogh, V; Dorronsoro, M; Travis, RC; Tjonneland, A; Brennan, P; Chang-Claude, J; Riboli, E; Conti, D; Stern, MC; Pike, MC; van Den Berg, D; Yuan, J.-, M; Hohensee, C; Jeppson, RP; Cancel-Tassin, G; Roupret, M; Comperat, E; Turman, C; de Vivo, I; Giovannucci, E; Hunter, DJ; Kraft, P; Lindstrom, S; Carta, A; Pavanello, S; Arici, C; Mastrangelo, G; Kamat, AM; Zhang, L; Gong, Y; Pu, X; Hutchinson, A; Burdett, L; Wheeler, WA; Karagas, MR; Johnson, A; Schned, A; Hosain, GMM; Schwenn, M; Kogevinas, M; Tardon, A; Serra, C; Carrato, A; Garcia-Closas, R; Lloreta, J; Andriole, G., Jr; Grubb, R., III; Black, A; Diver, WR; Gapstur, SM; Weinstein, S; Virtamo, J; Haiman, CA; Landi, MT; Caporaso, NE; Fraumeni, J.F., Jr; Vineis, P; Wu, X; Chanock, SJ; Silverman, DT; Prokunina-Olsson, L; Rothman, N; (2016) 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. Human molecular genetics, 25 (6). pp. 1203-1214. ISSN 0964-6906 DOI: https://doi.org/10.1093/hmg/ddv492

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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 < 1x 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 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 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 (r(2) = 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.

Item Type: Article
Faculty and Department: Faculty of Public Health and Policy > Dept of Social and Environmental Health Research
PubMed ID: 26732427
Web of Science ID: 372152900013
URI: http://researchonline.lshtm.ac.uk/id/eprint/4006406

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