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.

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 (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.

• Authors: 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 Cussenot, Simone 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 Jr, Robert Grubb 3rd, Amanda Black, W Ryan Diver, Susan M Gapstur, Stephanie Weinstein, Jarmo Virtamo, Christopher A Haiman, Maria Teresa Landi, Neil E Caporaso, Joseph F Fraumeni Jr, Paolo Vineis, Xifeng Wu, Stephen J Chanock, Debra T Silverman, Ludmila Prokunina-Olsson, Nathaniel Rothman
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 25 Issue 6 Pg. 1203-14 (Mar 15 2016) ISSN: 1460-2083 [Electronic] England
• PMID: 26732427 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural)
• Copyright: 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.

Chemical References

• Biomarkers, Tumor

Topics

• Biomarkers, Tumor (genetics)
• Case-Control Studies
• Chromosomes, Human, Pair 13
• Chromosomes, Human, Pair 20
• Female
• Genetic Association Studies
• Genetic Predisposition to Disease (genetics)
• Genome-Wide Association Study
• Humans
• Linkage Disequilibrium
• Male
• Polymorphism, Single Nucleotide
• Risk Factors
• Urinary Bladder Neoplasms (ethnology, genetics)
• White People (genetics)