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

TY - JOUR

T1 - 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

AU - Figueroa, Jonine D

AU - Middlebrooks, Candace D

AU - Banday, A Rouf

AU - Ye, Yuanqing

AU - Garcia-Closas, Montserrat

AU - Chatterjee, Nilanjan

AU - Koutros, Stella

AU - Kiemeney, Lambertus A

AU - Rafnar, Thorunn

AU - Bishop, Timothy

AU - Furberg, Helena

AU - Matullo, Giuseppe

AU - Golka, Klaus

AU - Gago-Dominguez, Manuela

AU - Taylor, Jack A

AU - Fletcher, Tony

AU - Siddiq, Afshan

AU - Cortessis, Victoria K

AU - Kooperberg, Charles

AU - Cussenot, Olivier

AU - Benhamou, Simone

AU - Prescott, Jennifer

AU - Porru, Stefano

AU - Dinney, Colin P

AU - Malats, Núria

AU - Baris, Dalsu

AU - Purdue, Mark P

AU - Jacobs, Eric J

AU - Albanes, Demetrius

AU - Wang, Zhaoming

AU - Chung, Charles C

AU - Vermeulen, Sita H

AU - Aben, Katja K

AU - Galesloot, Tessel E

AU - Thorleifsson, Gudmar

AU - Sulem, Patrick

AU - Stefansson, Kari

AU - Kiltie, Anne E

AU - Harland, Mark

AU - Teo, Mark

AU - Offit, Kenneth

AU - Vijai, Joseph

AU - Bajorin, Dean

AU - Kopp, Ryan

AU - Fiorito, Giovanni

AU - Guarrera, Simonetta

AU - Sacerdote, Carlotta

AU - Selinski, Silvia

AU - Hengstler, Jan G

AU - Gerullis, Holger

AU - Ovsiannikov, Daniel

AU - Blaszkewicz, Meinolf

AU - Castelao, Jose Esteban

AU - Calaza, Manuel

AU - Martinez, Maria Elena

AU - Cordeiro, Patricia

AU - Xu, Zongli

AU - Panduri, Vijayalakshmi

AU - Kumar, Rajiv

AU - Gurzau, Eugene

AU - Koppova, Kvetoslava

AU - Bueno-De-Mesquita, H Bas

AU - Ljungberg, Börje

AU - Clavel-Chapelon, Françoise

AU - Weiderpass, Elisabete

AU - Krogh, Vittorio

AU - Dorronsoro, Miren

AU - Travis, Ruth C

AU - Tjønneland, Anne

AU - Brennan, Paul

AU - Chang-Claude, Jenny

AU - Riboli, Elio

AU - Conti, David

AU - Stern, Marianna C

AU - Pike, Malcolm C

AU - Van Den Berg, David

AU - Yuan, Jian-Min

AU - Hohensee, Chancellor

AU - Jeppson, Rebecca P

AU - Cancel-Tassin, Geraldine

AU - Roupret, Morgan

AU - Comperat, Eva

AU - Turman, Constance

AU - De Vivo, Immaculata

AU - Giovannucci, Edward

AU - Hunter, David J

AU - Kraft, Peter

AU - Lindstrom, Sara

AU - Carta, Angela

AU - Pavanello, Sofia

AU - Arici, Cecilia

AU - Mastrangelo, Giuseppe

AU - Kamat, Ashish M

AU - Zhang, Liren

AU - Gong, Yilei

AU - Pu, Xia

AU - Hutchinson, Amy

AU - Burdett, Laurie

AU - Wheeler, William A

AU - Karagas, Margaret R

AU - Johnson, Alison

AU - Schned, Alan

AU - Monawar Hosain, G M

AU - Schwenn, Molly

AU - Kogevinas, Manolis

AU - Tardón, Adonina

AU - Serra, Consol

AU - Carrato, Alfredo

AU - García-Closas, Reina

AU - Lloreta, Josep

AU - Andriole, Gerald

AU - Grubb, Robert

AU - Black, Amanda

AU - Diver, W Ryan

AU - Gapstur, Susan M

AU - Weinstein, Stephanie

AU - Virtamo, Jarmo

AU - Haiman, Christopher A

AU - Landi, Maria Teresa

AU - Caporaso, Neil E

AU - Fraumeni, Joseph F

AU - Vineis, Paolo

AU - Wu, Xifeng

AU - Chanock, Stephen J

AU - Silverman, Debra T

AU - Prokunina-Olsson, Ludmila

AU - Rothman, Nathaniel

N1 - 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.

PY - 2016/3/15

Y1 - 2016/3/15

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddv492

DO - 10.1093/hmg/ddv492

M3 - SCORING: Journal article

C2 - 26732427

VL - 25

SP - 1203

EP - 1214

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 6

ER -