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

Jonine D. Figueroa, Candace D. Middlebrooks, A. Rouf Banday, Yuanqing Ye, Montserrat Garcia-Closas, Nilanjan Chatterjee, Stella Koutros, Lambertus A. Kiemeney, Thorunn Rafnar, Timothy Bishop, Helena Furberg, Giuseppe Matullo, Klaus Golka, Manuela Gago-Dominguez, Jack A. Taylor, Tony Fletcher, Afshan Siddiq, Victoria K. Cortessis, Charles Kooperberg, Olivier CussenotSimone Benhamou, Jennifer Prescott, Stefano Porru, Colin P. Dinney, Núria Malats, Dalsu Baris, Mark P. Purdue, Eric J. Jacobs, Demetrius Albanes, Zhaoming Wang, Charles C. Chung, Sita H. Vermeulen, Katja K. Aben, Tessel E. Galesloot, Gudmar Thorleifsson, Patrick Sulem, Kari Stefansson, Anne E. Kiltie, Mark Harland, Mark Teo, Kenneth Offit, Joseph Vijai, Dean Bajorin, Ryan Kopp, Giovanni Fiorito, Simonetta Guarrera, Carlotta Sacerdote, Silvia Selinski, Jan G. Hengstler, Holger Gerullis, Daniel Ovsiannikov, Meinolf Blaszkewicz, Jose Esteban Castelao, Manuel Calaza, Maria Elena Martinez, Patricia Cordeiro, Zongli Xu, Vijayalakshmi Panduri, Rajiv Kumar, Eugene Gurzau, Kvetoslava Koppova, H. Bas Bueno-De-Mesquita, Börje Ljungberg, Françoise Clavel-Chapelon, Elisabete Weiderpass, Vittorio Krogh, Miren Dorronsoro, Ruth C. Travis, Anne Tjønneland, Paul Brennan, Jenny Chang-Claude, Elio Riboli, David Conti, Marianna C. Stern, Malcolm C. Pike, David Van Den Berg, Jian Min Yuan, Chancellor Hohensee, Rebecca P. Jeppson, Geraldine Cancel-Tassin, Morgan Roupret, Eva Comperat, Constance Turman, Immaculata De Vivo, Edward Giovannucci, David J. Hunter, Peter Kraft, Sara Lindstrom, Angela Carta, Sofia Pavanello, Cecilia Arici, Giuseppe Mastrangelo, Ashish M. Kamat, Liren Zhang, Yilei Gong, Xia Pu, Amy Hutchinson, Laurie Burdett, William A. Wheeler, Margaret R. Karagas, Alison Johnson, Alan Schned, G. M. Monawar Hosain, Molly Schwenn, Manolis Kogevinas, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina García-Closas, Josep Lloreta, Gerald Andriole, Grubb Robert, Amanda Black, W. Ryan Diver, Susan M. Gapstur, Stephanie Weinstein, Jarmo Virtamo, Christopher A. Haiman, Maria Teresa Landi, Neil E. Caporaso, Fraumeni Joseph, Paolo Vineis, Xifeng Wu, Stephen J. Chanock, Debra T. Silverman, Ludmila Prokunina-Olsson, Nathaniel Rothman

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1203-1214
Number of pages12
JournalHuman molecular genetics
Volume25
Issue number6
DOIs
StatePublished - Aug 17 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    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., ... Rothman, N. (2015). 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), 1203-1214. https://doi.org/10.1093/hmg/ddv492