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.

Author(s): 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,  Castelao JE,  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,  Tjønneland A,  Brennan P,  Chang-Claude J,  Riboli E,  Conti D,  Stern MC,  Pike MC,  Van Den Berg D,  Yuan JM,  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,  Monawar Hosain GM,  Schwenn M,  Kogevinas M,  Tardón A,  Serra C,  Carrato A,  García-Closas R,  Lloreta J,  Andriole G Jr,  Grubb R 3rd,  Black A,  Diver WR,  Gapstur SM,  Weinstein S,  Virtamo J,  Haiman CA,  Landi MT,  Caporaso NE,  Fraumeni JF Jr,  Vineis P,  Wu X,  Chanock SJ,  Silverman DT,  Prokunina-Olsson L,  Rothman N

Journal: Hum Mol Genet

Date: 2016 Mar 15

Major Program(s) or Research Group(s): PLCO

PubMed ID: 26732427

PMC ID: PMC4817084

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.