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 Barnes, Giuseppe Matullo, Klaus Golka, Manuela Gago-Dominguez, Jack 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 Scaredote, Silvia Selinski, Jan G Hengstler, Holger Gerullis, Daniel Ovsianikov, Meinolf Blaszkewicz, Jose E Castelao, Manuel Calaza, Maria E Martinez, Patricia Cordeiro, Zongli Xu, Vijji 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 Rodabough, Geraldine Cancel-Tassin, Morgan Roupret, Eva Comperat, Constance Chen, 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, Gm Monawar Hosain, Molly Schwenn, Manolis Kogevinas, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina García-Closas, Josep Lloreta, Gerald Andriole, Robert Grubb, Amanda Black, W Ryan Diver, Susan M Gapstur, Stephanie Weinstein, Jarmo Virtamo, Christopher A Haiman, Maria Teresa Landi, Neil E Caporaso, Joseph F Fraumeni, Paolo Vineis, Xifeng Wu, Stephen J Chanock, Debra T Silverman, Ludmila Prokunina-Olsson, Nathaniel Rothman

Research output: Contribution to journalArticlepeer-review

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 6,911 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 5,551 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 to 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.

Original languageEnglish
JournalHuman Molecular Genetics
DOIs
Publication statusPublished - 4 Jan 2016

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