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 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; 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

doi:10.1093/hmg/ddv492

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 journal › Article › peer-review

27 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 language	English (US)
Pages (from-to)	1203-1214
Number of pages	12
Journal	Human molecular genetics
Volume	25
Issue number	6
DOIs	https://doi.org/10.1093/hmg/ddv492
State	Published - Aug 17 2015
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

Access to Document

10.1093/hmg/ddv492

Cite this

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

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. / Figueroa, Jonine D.; Middlebrooks, Candace D.; Banday, A. Rouf et al.

In: Human molecular genetics, Vol. 25, No. 6, 17.08.2015, p. 1203-1214.

Research output: Contribution to journal › Article › peer-review

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, Robert, G, Black, A, Diver, WR, Gapstur, SM, Weinstein, S, Virtamo, J, Haiman, CA, Landi, MT, Caporaso, NE, Joseph, F, Vineis, P, Wu, X, Chanock, SJ, Silverman, DT, Prokunina-Olsson, L & 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, vol. 25, no. 6, pp. 1203-1214. https://doi.org/10.1093/hmg/ddv492

@article{f0430ed2dd964436b87a3ae3318a458b,

title = "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 (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.",

author = "Figueroa, {Jonine D.} and Middlebrooks, {Candace D.} and Banday, {A. Rouf} and Yuanqing Ye and Montserrat Garcia-Closas and Nilanjan Chatterjee and Stella Koutros and Kiemeney, {Lambertus A.} and Thorunn Rafnar and Timothy Bishop and Helena Furberg and Giuseppe Matullo and Klaus Golka and Manuela Gago-Dominguez and Taylor, {Jack A.} and Tony Fletcher and Afshan Siddiq and Cortessis, {Victoria K.} and Charles Kooperberg and Olivier Cussenot and Simone Benhamou and Jennifer Prescott and Stefano Porru and Dinney, {Colin P.} and N{\'u}ria Malats and Dalsu Baris and Purdue, {Mark P.} and Jacobs, {Eric J.} and Demetrius Albanes and Zhaoming Wang and Chung, {Charles C.} and Vermeulen, {Sita H.} and Aben, {Katja K.} and Galesloot, {Tessel E.} and Gudmar Thorleifsson and Patrick Sulem and Kari Stefansson and Kiltie, {Anne E.} and Mark Harland and Mark Teo and Kenneth Offit and Joseph Vijai and Dean Bajorin and Ryan Kopp and Giovanni Fiorito and Simonetta Guarrera and Carlotta Sacerdote and Silvia Selinski and Hengstler, {Jan G.} and Holger Gerullis and Daniel Ovsiannikov and Meinolf Blaszkewicz and Castelao, {Jose Esteban} and Manuel Calaza and Martinez, {Maria Elena} and Patricia Cordeiro and Zongli Xu and Vijayalakshmi Panduri and Rajiv Kumar and Eugene Gurzau and Kvetoslava Koppova and Bueno-De-Mesquita, {H. Bas} and B{\"o}rje Ljungberg and Fran{\c c}oise Clavel-Chapelon and Elisabete Weiderpass and Vittorio Krogh and Miren Dorronsoro and Travis, {Ruth C.} and Anne Tj{\o}nneland and Paul Brennan and Jenny Chang-Claude and Elio Riboli and David Conti and Stern, {Marianna C.} and Pike, {Malcolm C.} and {Van Den Berg}, David and Yuan, {Jian Min} and Chancellor Hohensee and Jeppson, {Rebecca P.} and Geraldine Cancel-Tassin and Morgan Roupret and Eva Comperat and Constance Turman and {De Vivo}, Immaculata and Edward Giovannucci and Hunter, {David J.} and Peter Kraft and Sara Lindstrom and Angela Carta and Sofia Pavanello and Cecilia Arici and Giuseppe Mastrangelo and Kamat, {Ashish M.} and Liren Zhang and Yilei Gong and Xia Pu and Amy Hutchinson and Laurie Burdett and Wheeler, {William A.} and Karagas, {Margaret R.} and Alison Johnson and Alan Schned and {Monawar Hosain}, {G. M.} and Molly Schwenn and Manolis Kogevinas and Adonina Tard{\'o}n and Consol Serra and Alfredo Carrato and Reina Garc{\'i}a-Closas and Josep Lloreta and Gerald Andriole and Grubb Robert and Amanda Black and Diver, {W. Ryan} and Gapstur, {Susan M.} and Stephanie Weinstein and Jarmo Virtamo and Haiman, {Christopher A.} and Landi, {Maria Teresa} and Caporaso, {Neil E.} and Fraumeni Joseph and Paolo Vineis and Xifeng Wu and Chanock, {Stephen J.} and Silverman, {Debra T.} and Ludmila Prokunina-Olsson and Nathaniel Rothman",

note = "Funding Information: See Supplementary Material for funding details. The authors acknowledge the following: Marie Audouin, C{\'e}cile Gaffory, Val{\'e}rie Ondet; Leslie Carroll (Information Management Services, Silver Spring, MD, USA); Gemma Casta{\~n}o-Vinyals (Institut Municipal d{\textquoteright}Investigaci{\'o} M{\`e}dica, Barcelona, Spain); Francisco Fern{\'a}ndez (Institut Municipal d{\textquoteright}Investigaci{\'o} M{\`e}dica, Barcelona, Spain); Anna McIntosh (Westat, Inc., Rockville, MD, USA); Robert Saal (Westat, Rockville, MD, USA); Francisco Real [Spanish National Cancer Research Centre (CNIO), Madrid, Spain]; Maria Sala (Institut Municipal d{\textquoteright}Investigaci{\'o} M{\`e}dica, Barcelona, Spain); Kirk Snyder (Information Management Services, Inc., Silver Spring, MD); Anne Taylor (Information Management Services, Inc., Silver Spring, MD); Montserrat Tor{\`a} (Institut Municipal d{\textquoteright}Investigaci{\'o} M{\`e}dica, Barcelona, Spain); JaneWang (Information Management Services, Silver Spring, MD, USA). WHI Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller. Clinical Coordinating Center: Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg. Investigators and Academic Centers: (Brigham and Women{\textquoteright}s Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/ Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/ Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. Women{\textquoteright}s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. For a list of all the investigators who have contributed to WHI science, please visit: https://cleo.whi.org/researchers/SitePages/ Write%20a%20Paper.aspx. The Memorial Sloan Kettering investigators gratefully acknowledge the MSK Cancer Center Support Grant/Core Grant (P30 CA008748).",

year = "2015",

month = aug,

day = "17",

doi = "10.1093/hmg/ddv492",

language = "English (US)",

volume = "25",

pages = "1203--1214",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "6",

}

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 - Robert, Grubb

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 - Joseph, Fraumeni

AU - Vineis, Paolo

AU - Wu, Xifeng

AU - Chanock, Stephen J.

AU - Silverman, Debra T.

AU - Prokunina-Olsson, Ludmila

AU - Rothman, Nathaniel

N1 - Funding Information: See Supplementary Material for funding details. The authors acknowledge the following: Marie Audouin, Cécile Gaffory, Valérie Ondet; Leslie Carroll (Information Management Services, Silver Spring, MD, USA); Gemma Castaño-Vinyals (Institut Municipal d’Investigació Mèdica, Barcelona, Spain); Francisco Fernández (Institut Municipal d’Investigació Mèdica, Barcelona, Spain); Anna McIntosh (Westat, Inc., Rockville, MD, USA); Robert Saal (Westat, Rockville, MD, USA); Francisco Real [Spanish National Cancer Research Centre (CNIO), Madrid, Spain]; Maria Sala (Institut Municipal d’Investigació Mèdica, Barcelona, Spain); Kirk Snyder (Information Management Services, Inc., Silver Spring, MD); Anne Taylor (Information Management Services, Inc., Silver Spring, MD); Montserrat Torà (Institut Municipal d’Investigació Mèdica, Barcelona, Spain); JaneWang (Information Management Services, Silver Spring, MD, USA). WHI Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller. Clinical Coordinating Center: Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg. Investigators and Academic Centers: (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/ Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/ Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. For a list of all the investigators who have contributed to WHI science, please visit: https://cleo.whi.org/researchers/SitePages/ Write%20a%20Paper.aspx. The Memorial Sloan Kettering investigators gratefully acknowledge the MSK Cancer Center Support Grant/Core Grant (P30 CA008748).

PY - 2015/8/17

Y1 - 2015/8/17

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 (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.

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 (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.

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U2 - 10.1093/hmg/ddv492

DO - 10.1093/hmg/ddv492

M3 - Article

C2 - 26732427

AN - SCOPUS:84960105525

VL - 25

SP - 1203

EP - 1214

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 6

ER -

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

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