Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1

Dylan M. Glubb, Mel J. Maranian, Kyriaki Michailidou, Karen A. Pooley, Kerstin B. Meyer, Siddhartha Kar, Saskia Carlebur, Martin O'Reilly, Joshua A. Betts, Kristine M. Hillman, Susanne Kaufmann, Jonathan Beesley, Sander Canisius, John L. Hopper, Melissa C. Southey, Helen Tsimiklis, Carmel Apicella, Marjanka K. Schmidt, Annegien Broeks, Frans B. Hogervorst & 195 others C. Ellen Van Der Schoot, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Peter A. Fasching, Matthias Ruebner, Arif B. Ekici, Matthias W. Beckmann, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Paul D P Pharoah, Manjeet K. Bolla, Qin Wang, Joe Dennis, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Barbara Burwinkel, Frederik Marme, Rongxi Yang, Harald Surowy, Pascal Guénel, Thérèse Truong, Florence Menegaux, Marie Sanchez, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Anna González-Neira, Javier Benitez, M. Pilar Zamora, Jose Ignacio Arias Perez, Hoda Anton-Culver, Susan L. Neuhausen, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Rita K. Schmutzler, Hiltrud Brauch, Yon Dschun Ko, Thomas Brüning, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Hideo Tanaka, Thilo Dörk, Natalia V. Bogdanova, Sonja Helbig, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli Matti Kosma, Jaana M. Hartikainen, Anna H. Wu, Chiu Chen Tseng, David Van Den Berg, Daniel O. Stram, Diether Lambrechts, Hui Zhao, Caroline Weltens, Erik Van Limbergen, Jenny Chang-Claude, Dieter Flesch-Janys, Anja Rudolph, Petra Seibold, Paolo Radice, Paolo Peterlongo, Monica Barile, Fabio Capra, Fergus J. Couch, Janet E. Olson, Emily Hallberg, Celine Vachon, Graham G. Giles, Roger L. Milne, Catriona McLean, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Soo Hwang Teo, Cheng Har Yip, Mee Hoong See, Belinda Cornes, Ching Yu Cheng, M. Kamran Ikram, Vessela Kristensen, Wei Zheng, Sandra L. Halverson, Martha Shrubsole, Jirong Long, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Peter Devilee, Robert A E M Tollenaar, Caroline Seynaeve, Christi J. Van Asperen, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Kamila Czene, Daniel Klevebring, Hatef Darabi, Mikael Eriksson, Maartje J. Hooning, Antoinette Hollestelle, John W M Martens, J. Margriet Collée, Per Hall, Jingmei Li, Keith Humphreys, Xiao Ou Shu, Wei Lu, Yu Tang Gao, Hui Cai, Angela Cox, Simon S. Cross, Malcolm W R Reed, William Blot, Lisa B. Signorello, Qiuyin Cai, Mitul Shah, Maya Ghoussaini, Daehee Kang, Ji Yeob Choi, Sue K. Park, Dong Young Noh, Mikael Hartman, Hui Miao, Wei Yen Lim, Anthony Tang, Ute Hamann, Diana Torres, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Curtis Olswold, Susan Slager, Amanda E. Toland, Drakoulis Yannoukakos, Chen Yang Shen, Pei Ei Wu, Jyh Cherng Yu, Ming Feng Hou, Anthony Swerdlow, Alan Ashworth, Nick Orr, Michael Jones, Guillermo Pita, M. Rosario Alonso, Nuria Álvarez, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Catherine S. Healey, Melissa A. Brown, Bruce A J Ponder, Georgia Chenevix-Trench, Deborah J. Thompson, Stacey L. Edwards, Douglas F. Easton, Alison M. Dunning, Juliet D. French

Research output: Contribution to journalArticle

Abstract

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER+: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10-44) and estrogen-receptor-negative (ER-: OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10-4) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10-5]) and five variants composing iCHAV3 (lead rs11949391; ER+: OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10-4). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

Original languageEnglish (US)
Pages (from-to)5-20
Number of pages16
JournalAmerican Journal of Human Genetics
Volume96
Issue number1
DOIs
StatePublished - Jan 8 2015
Externally publishedYes

Fingerprint

Breast Neoplasms
Alleles
Odds Ratio
Confidence Intervals
Estrogen Receptors
Neoplasms
Chromatin Immunoprecipitation
Genome-Wide Association Study
Chromatin
Single Nucleotide Polymorphism
Cell Survival
Logistic Models
Regression Analysis

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1. / Glubb, Dylan M.; Maranian, Mel J.; Michailidou, Kyriaki; Pooley, Karen A.; Meyer, Kerstin B.; Kar, Siddhartha; Carlebur, Saskia; O'Reilly, Martin; Betts, Joshua A.; Hillman, Kristine M.; Kaufmann, Susanne; Beesley, Jonathan; Canisius, Sander; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.; Van Der Schoot, C. Ellen; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A.; Ruebner, Matthias; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; Dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Pharoah, Paul D P; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; González-Neira, Anna; Benitez, Javier; Zamora, M. Pilar; Arias Perez, Jose Ignacio; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Ko, Yon Dschun; Brüning, Thomas; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tanaka, Hideo; Dörk, Thilo; Bogdanova, Natalia V.; Helbig, Sonja; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli Matti; Hartikainen, Jaana M.; Wu, Anna H.; Tseng, Chiu Chen; Van Den Berg, David; Stram, Daniel O.; Lambrechts, Diether; Zhao, Hui; Weltens, Caroline; Van Limbergen, Erik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Radice, Paolo; Peterlongo, Paolo; Barile, Monica; Capra, Fabio; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; See, Mee Hoong; Cornes, Belinda; Cheng, Ching Yu; Ikram, M. Kamran; Kristensen, Vessela; Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J.; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Klevebring, Daniel; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W M; Collée, J. Margriet; Hall, Per; Li, Jingmei; Humphreys, Keith; Shu, Xiao Ou; Lu, Wei; Gao, Yu Tang; Cai, Hui; Cox, Angela; Cross, Simon S.; Reed, Malcolm W R; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Shah, Mitul; Ghoussaini, Maya; Kang, Daehee; Choi, Ji Yeob; Park, Sue K.; Noh, Dong Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Tang, Anthony; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Olswold, Curtis; Slager, Susan; Toland, Amanda E.; Yannoukakos, Drakoulis; Shen, Chen Yang; Wu, Pei Ei; Yu, Jyh Cherng; Hou, Ming Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Pita, Guillermo; Alonso, M. Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S.; Brown, Melissa A.; Ponder, Bruce A J; Chenevix-Trench, Georgia; Thompson, Deborah J.; Edwards, Stacey L.; Easton, Douglas F.; Dunning, Alison M.; French, Juliet D.

In: American Journal of Human Genetics, Vol. 96, No. 1, 08.01.2015, p. 5-20.

Research output: Contribution to journalArticle

Glubb, DM, Maranian, MJ, Michailidou, K, Pooley, KA, Meyer, KB, Kar, S, Carlebur, S, O'Reilly, M, Betts, JA, Hillman, KM, Kaufmann, S, Beesley, J, Canisius, S, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Schmidt, MK, Broeks, A, Hogervorst, FB, Van Der Schoot, CE, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Fasching, PA, Ruebner, M, Ekici, AB, Beckmann, MW, Peto, J, Dos-Santos-Silva, I, Fletcher, O, Johnson, N, Pharoah, PDP, Bolla, MK, Wang, Q, Dennis, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Burwinkel, B, Marme, F, Yang, R, Surowy, H, Guénel, P, Truong, T, Menegaux, F, Sanchez, M, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, González-Neira, A, Benitez, J, Zamora, MP, Arias Perez, JI, Anton-Culver, H, Neuhausen, SL, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Meindl, A, Schmutzler, RK, Brauch, H, Ko, YD, Brüning, T, Nevanlinna, H, Muranen, TA, Aittomäki, K, Blomqvist, C, Matsuo, K, Ito, H, Iwata, H, Tanaka, H, Dörk, T, Bogdanova, NV, Helbig, S, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, Lambrechts, D, Zhao, H, Weltens, C, Van Limbergen, E, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Seibold, P, Radice, P, Peterlongo, P, Barile, M, Capra, F, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Giles, GG, Milne, RL, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Goldberg, MS, Labrèche, F, Dumont, M, Teo, SH, Yip, CH, See, MH, Cornes, B, Cheng, CY, Ikram, MK, Kristensen, V, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, García-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Klevebring, D, Darabi, H, Eriksson, M, Hooning, MJ, Hollestelle, A, Martens, JWM, Collée, JM, Hall, P, Li, J, Humphreys, K, Shu, XO, Lu, W, Gao, YT, Cai, H, Cox, A, Cross, SS, Reed, MWR, Blot, W, Signorello, LB, Cai, Q, Shah, M, Ghoussaini, M, Kang, D, Choi, JY, Park, SK, Noh, DY, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Olswold, C, Slager, S, Toland, AE, Yannoukakos, D, Shen, CY, Wu, PE, Yu, JC, Hou, MF, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Pita, G, Alonso, MR, Álvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Brown, MA, Ponder, BAJ, Chenevix-Trench, G, Thompson, DJ, Edwards, SL, Easton, DF, Dunning, AM & French, JD 2015, 'Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1', American Journal of Human Genetics, vol. 96, no. 1, pp. 5-20. https://doi.org/10.1016/j.ajhg.2014.11.009
Glubb, Dylan M. ; Maranian, Mel J. ; Michailidou, Kyriaki ; Pooley, Karen A. ; Meyer, Kerstin B. ; Kar, Siddhartha ; Carlebur, Saskia ; O'Reilly, Martin ; Betts, Joshua A. ; Hillman, Kristine M. ; Kaufmann, Susanne ; Beesley, Jonathan ; Canisius, Sander ; Hopper, John L. ; Southey, Melissa C. ; Tsimiklis, Helen ; Apicella, Carmel ; Schmidt, Marjanka K. ; Broeks, Annegien ; Hogervorst, Frans B. ; Van Der Schoot, C. Ellen ; Muir, Kenneth ; Lophatananon, Artitaya ; Stewart-Brown, Sarah ; Siriwanarangsan, Pornthep ; Fasching, Peter A. ; Ruebner, Matthias ; Ekici, Arif B. ; Beckmann, Matthias W. ; Peto, Julian ; Dos-Santos-Silva, Isabel ; Fletcher, Olivia ; Johnson, Nichola ; Pharoah, Paul D P ; Bolla, Manjeet K. ; Wang, Qin ; Dennis, Joe ; Sawyer, Elinor J. ; Tomlinson, Ian ; Kerin, Michael J. ; Miller, Nicola ; Burwinkel, Barbara ; Marme, Frederik ; Yang, Rongxi ; Surowy, Harald ; Guénel, Pascal ; Truong, Thérèse ; Menegaux, Florence ; Sanchez, Marie ; Bojesen, Stig E. ; Nordestgaard, Børge G. ; Nielsen, Sune F. ; Flyger, Henrik ; González-Neira, Anna ; Benitez, Javier ; Zamora, M. Pilar ; Arias Perez, Jose Ignacio ; Anton-Culver, Hoda ; Neuhausen, Susan L. ; Brenner, Hermann ; Dieffenbach, Aida Karina ; Arndt, Volker ; Stegmaier, Christa ; Meindl, Alfons ; Schmutzler, Rita K. ; Brauch, Hiltrud ; Ko, Yon Dschun ; Brüning, Thomas ; Nevanlinna, Heli ; Muranen, Taru A. ; Aittomäki, Kristiina ; Blomqvist, Carl ; Matsuo, Keitaro ; Ito, Hidemi ; Iwata, Hiroji ; Tanaka, Hideo ; Dörk, Thilo ; Bogdanova, Natalia V. ; Helbig, Sonja ; Lindblom, Annika ; Margolin, Sara ; Mannermaa, Arto ; Kataja, Vesa ; Kosma, Veli Matti ; Hartikainen, Jaana M. ; Wu, Anna H. ; Tseng, Chiu Chen ; Van Den Berg, David ; Stram, Daniel O. ; Lambrechts, Diether ; Zhao, Hui ; Weltens, Caroline ; Van Limbergen, Erik ; Chang-Claude, Jenny ; Flesch-Janys, Dieter ; Rudolph, Anja ; Seibold, Petra ; Radice, Paolo ; Peterlongo, Paolo ; Barile, Monica ; Capra, Fabio ; Couch, Fergus J. ; Olson, Janet E. ; Hallberg, Emily ; Vachon, Celine ; Giles, Graham G. ; Milne, Roger L. ; McLean, Catriona ; Haiman, Christopher A. ; Henderson, Brian E. ; Schumacher, Fredrick ; Le Marchand, Loic ; Simard, Jacques ; Goldberg, Mark S. ; Labrèche, France ; Dumont, Martine ; Teo, Soo Hwang ; Yip, Cheng Har ; See, Mee Hoong ; Cornes, Belinda ; Cheng, Ching Yu ; Ikram, M. Kamran ; Kristensen, Vessela ; Zheng, Wei ; Halverson, Sandra L. ; Shrubsole, Martha ; Long, Jirong ; Winqvist, Robert ; Pylkäs, Katri ; Jukkola-Vuorinen, Arja ; Kauppila, Saila ; Andrulis, Irene L. ; Knight, Julia A. ; Glendon, Gord ; Tchatchou, Sandrine ; Devilee, Peter ; Tollenaar, Robert A E M ; Seynaeve, Caroline ; Van Asperen, Christi J. ; García-Closas, Montserrat ; Figueroa, Jonine ; Chanock, Stephen J. ; Lissowska, Jolanta ; Czene, Kamila ; Klevebring, Daniel ; Darabi, Hatef ; Eriksson, Mikael ; Hooning, Maartje J. ; Hollestelle, Antoinette ; Martens, John W M ; Collée, J. Margriet ; Hall, Per ; Li, Jingmei ; Humphreys, Keith ; Shu, Xiao Ou ; Lu, Wei ; Gao, Yu Tang ; Cai, Hui ; Cox, Angela ; Cross, Simon S. ; Reed, Malcolm W R ; Blot, William ; Signorello, Lisa B. ; Cai, Qiuyin ; Shah, Mitul ; Ghoussaini, Maya ; Kang, Daehee ; Choi, Ji Yeob ; Park, Sue K. ; Noh, Dong Young ; Hartman, Mikael ; Miao, Hui ; Lim, Wei Yen ; Tang, Anthony ; Hamann, Ute ; Torres, Diana ; Jakubowska, Anna ; Lubinski, Jan ; Jaworska, Katarzyna ; Durda, Katarzyna ; Sangrajrang, Suleeporn ; Gaborieau, Valerie ; Brennan, Paul ; McKay, James ; Olswold, Curtis ; Slager, Susan ; Toland, Amanda E. ; Yannoukakos, Drakoulis ; Shen, Chen Yang ; Wu, Pei Ei ; Yu, Jyh Cherng ; Hou, Ming Feng ; Swerdlow, Anthony ; Ashworth, Alan ; Orr, Nick ; Jones, Michael ; Pita, Guillermo ; Alonso, M. Rosario ; Álvarez, Nuria ; Herrero, Daniel ; Tessier, Daniel C. ; Vincent, Daniel ; Bacot, Francois ; Luccarini, Craig ; Baynes, Caroline ; Ahmed, Shahana ; Healey, Catherine S. ; Brown, Melissa A. ; Ponder, Bruce A J ; Chenevix-Trench, Georgia ; Thompson, Deborah J. ; Edwards, Stacey L. ; Easton, Douglas F. ; Dunning, Alison M. ; French, Juliet D. / Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1. In: American Journal of Human Genetics. 2015 ; Vol. 96, No. 1. pp. 5-20.
@article{56426e5343cf4f148994a34e47d09bfb,
title = "Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1",
abstract = "Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER+: odds ratio [OR] = 1.24, 95{\%} confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10-44) and estrogen-receptor-negative (ER-: OR = 1.10, 95{\%} CI = 1.05-1.15, ptrend = 3.0 × 10-4) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10-5]) and five variants composing iCHAV3 (lead rs11949391; ER+: OR = 0.90, 95{\%} CI = 0.87-0.93, pcond = 1.4 × 10-4). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.",
author = "Glubb, {Dylan M.} and Maranian, {Mel J.} and Kyriaki Michailidou and Pooley, {Karen A.} and Meyer, {Kerstin B.} and Siddhartha Kar and Saskia Carlebur and Martin O'Reilly and Betts, {Joshua A.} and Hillman, {Kristine M.} and Susanne Kaufmann and Jonathan Beesley and Sander Canisius and Hopper, {John L.} and Southey, {Melissa C.} and Helen Tsimiklis and Carmel Apicella and Schmidt, {Marjanka K.} and Annegien Broeks and Hogervorst, {Frans B.} and {Van Der Schoot}, {C. Ellen} and Kenneth Muir and Artitaya Lophatananon and Sarah Stewart-Brown and Pornthep Siriwanarangsan and Fasching, {Peter A.} and Matthias Ruebner and Ekici, {Arif B.} and Beckmann, {Matthias W.} and Julian Peto and Isabel Dos-Santos-Silva and Olivia Fletcher and Nichola Johnson and Pharoah, {Paul D P} and Bolla, {Manjeet K.} and Qin Wang and Joe Dennis and Sawyer, {Elinor J.} and Ian Tomlinson and Kerin, {Michael J.} and Nicola Miller and Barbara Burwinkel and Frederik Marme and Rongxi Yang and Harald Surowy and Pascal Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Florence Menegaux and Marie Sanchez and Bojesen, {Stig E.} and Nordestgaard, {B{\o}rge G.} and Nielsen, {Sune F.} and Henrik Flyger and Anna Gonz{\'a}lez-Neira and Javier Benitez and Zamora, {M. Pilar} and {Arias Perez}, {Jose Ignacio} and Hoda Anton-Culver and Neuhausen, {Susan L.} and Hermann Brenner and Dieffenbach, {Aida Karina} and Volker Arndt and Christa Stegmaier and Alfons Meindl and Schmutzler, {Rita K.} and Hiltrud Brauch and Ko, {Yon Dschun} and Thomas Br{\"u}ning and Heli Nevanlinna and Muranen, {Taru A.} and Kristiina Aittom{\"a}ki and Carl Blomqvist and Keitaro Matsuo and Hidemi Ito and Hiroji Iwata and Hideo Tanaka and Thilo D{\"o}rk and Bogdanova, {Natalia V.} and Sonja Helbig and Annika Lindblom and Sara Margolin and Arto Mannermaa and Vesa Kataja and Kosma, {Veli Matti} and Hartikainen, {Jaana M.} and Wu, {Anna H.} and Tseng, {Chiu Chen} and {Van Den Berg}, David and Stram, {Daniel O.} and Diether Lambrechts and Hui Zhao and Caroline Weltens and {Van Limbergen}, Erik and Jenny Chang-Claude and Dieter Flesch-Janys and Anja Rudolph and Petra Seibold and Paolo Radice and Paolo Peterlongo and Monica Barile and Fabio Capra and Couch, {Fergus J.} and Olson, {Janet E.} and Emily Hallberg and Celine Vachon and Giles, {Graham G.} and Milne, {Roger L.} and Catriona McLean and Haiman, {Christopher A.} and Henderson, {Brian E.} and Fredrick Schumacher and {Le Marchand}, Loic and Jacques Simard and Goldberg, {Mark S.} and France Labr{\`e}che and Martine Dumont and Teo, {Soo Hwang} and Yip, {Cheng Har} and See, {Mee Hoong} and Belinda Cornes and Cheng, {Ching Yu} and Ikram, {M. Kamran} and Vessela Kristensen and Wei Zheng and Halverson, {Sandra L.} and Martha Shrubsole and Jirong Long and Robert Winqvist and Katri Pylk{\"a}s and Arja Jukkola-Vuorinen and Saila Kauppila and Andrulis, {Irene L.} and Knight, {Julia A.} and Gord Glendon and Sandrine Tchatchou and Peter Devilee and Tollenaar, {Robert A E M} and Caroline Seynaeve and {Van Asperen}, {Christi J.} and Montserrat Garc{\'i}a-Closas and Jonine Figueroa and Chanock, {Stephen J.} and Jolanta Lissowska and Kamila Czene and Daniel Klevebring and Hatef Darabi and Mikael Eriksson and Hooning, {Maartje J.} and Antoinette Hollestelle and Martens, {John W M} and Coll{\'e}e, {J. Margriet} and Per Hall and Jingmei Li and Keith Humphreys and Shu, {Xiao Ou} and Wei Lu and Gao, {Yu Tang} and Hui Cai and Angela Cox and Cross, {Simon S.} and Reed, {Malcolm W R} and William Blot and Signorello, {Lisa B.} and Qiuyin Cai and Mitul Shah and Maya Ghoussaini and Daehee Kang and Choi, {Ji Yeob} and Park, {Sue K.} and Noh, {Dong Young} and Mikael Hartman and Hui Miao and Lim, {Wei Yen} and Anthony Tang and Ute Hamann and Diana Torres and Anna Jakubowska and Jan Lubinski and Katarzyna Jaworska and Katarzyna Durda and Suleeporn Sangrajrang and Valerie Gaborieau and Paul Brennan and James McKay and Curtis Olswold and Susan Slager and Toland, {Amanda E.} and Drakoulis Yannoukakos and Shen, {Chen Yang} and Wu, {Pei Ei} and Yu, {Jyh Cherng} and Hou, {Ming Feng} and Anthony Swerdlow and Alan Ashworth and Nick Orr and Michael Jones and Guillermo Pita and Alonso, {M. Rosario} and Nuria {\'A}lvarez and Daniel Herrero and Tessier, {Daniel C.} and Daniel Vincent and Francois Bacot and Craig Luccarini and Caroline Baynes and Shahana Ahmed and Healey, {Catherine S.} and Brown, {Melissa A.} and Ponder, {Bruce A J} and Georgia Chenevix-Trench and Thompson, {Deborah J.} and Edwards, {Stacey L.} and Easton, {Douglas F.} and Dunning, {Alison M.} and French, {Juliet D.}",
year = "2015",
month = "1",
day = "8",
doi = "10.1016/j.ajhg.2014.11.009",
language = "English (US)",
volume = "96",
pages = "5--20",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1

AU - Glubb, Dylan M.

AU - Maranian, Mel J.

AU - Michailidou, Kyriaki

AU - Pooley, Karen A.

AU - Meyer, Kerstin B.

AU - Kar, Siddhartha

AU - Carlebur, Saskia

AU - O'Reilly, Martin

AU - Betts, Joshua A.

AU - Hillman, Kristine M.

AU - Kaufmann, Susanne

AU - Beesley, Jonathan

AU - Canisius, Sander

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Tsimiklis, Helen

AU - Apicella, Carmel

AU - Schmidt, Marjanka K.

AU - Broeks, Annegien

AU - Hogervorst, Frans B.

AU - Van Der Schoot, C. Ellen

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Stewart-Brown, Sarah

AU - Siriwanarangsan, Pornthep

AU - Fasching, Peter A.

AU - Ruebner, Matthias

AU - Ekici, Arif B.

AU - Beckmann, Matthias W.

AU - Peto, Julian

AU - Dos-Santos-Silva, Isabel

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Pharoah, Paul D P

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dennis, Joe

AU - Sawyer, Elinor J.

AU - Tomlinson, Ian

AU - Kerin, Michael J.

AU - Miller, Nicola

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Yang, Rongxi

AU - Surowy, Harald

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Menegaux, Florence

AU - Sanchez, Marie

AU - Bojesen, Stig E.

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Flyger, Henrik

AU - González-Neira, Anna

AU - Benitez, Javier

AU - Zamora, M. Pilar

AU - Arias Perez, Jose Ignacio

AU - Anton-Culver, Hoda

AU - Neuhausen, Susan L.

AU - Brenner, Hermann

AU - Dieffenbach, Aida Karina

AU - Arndt, Volker

AU - Stegmaier, Christa

AU - Meindl, Alfons

AU - Schmutzler, Rita K.

AU - Brauch, Hiltrud

AU - Ko, Yon Dschun

AU - Brüning, Thomas

AU - Nevanlinna, Heli

AU - Muranen, Taru A.

AU - Aittomäki, Kristiina

AU - Blomqvist, Carl

AU - Matsuo, Keitaro

AU - Ito, Hidemi

AU - Iwata, Hiroji

AU - Tanaka, Hideo

AU - Dörk, Thilo

AU - Bogdanova, Natalia V.

AU - Helbig, Sonja

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Kosma, Veli Matti

AU - Hartikainen, Jaana M.

AU - Wu, Anna H.

AU - Tseng, Chiu Chen

AU - Van Den Berg, David

AU - Stram, Daniel O.

AU - Lambrechts, Diether

AU - Zhao, Hui

AU - Weltens, Caroline

AU - Van Limbergen, Erik

AU - Chang-Claude, Jenny

AU - Flesch-Janys, Dieter

AU - Rudolph, Anja

AU - Seibold, Petra

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Barile, Monica

AU - Capra, Fabio

AU - Couch, Fergus J.

AU - Olson, Janet E.

AU - Hallberg, Emily

AU - Vachon, Celine

AU - Giles, Graham G.

AU - Milne, Roger L.

AU - McLean, Catriona

AU - Haiman, Christopher A.

AU - Henderson, Brian E.

AU - Schumacher, Fredrick

AU - Le Marchand, Loic

AU - Simard, Jacques

AU - Goldberg, Mark S.

AU - Labrèche, France

AU - Dumont, Martine

AU - Teo, Soo Hwang

AU - Yip, Cheng Har

AU - See, Mee Hoong

AU - Cornes, Belinda

AU - Cheng, Ching Yu

AU - Ikram, M. Kamran

AU - Kristensen, Vessela

AU - Zheng, Wei

AU - Halverson, Sandra L.

AU - Shrubsole, Martha

AU - Long, Jirong

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Jukkola-Vuorinen, Arja

AU - Kauppila, Saila

AU - Andrulis, Irene L.

AU - Knight, Julia A.

AU - Glendon, Gord

AU - Tchatchou, Sandrine

AU - Devilee, Peter

AU - Tollenaar, Robert A E M

AU - Seynaeve, Caroline

AU - Van Asperen, Christi J.

AU - García-Closas, Montserrat

AU - Figueroa, Jonine

AU - Chanock, Stephen J.

AU - Lissowska, Jolanta

AU - Czene, Kamila

AU - Klevebring, Daniel

AU - Darabi, Hatef

AU - Eriksson, Mikael

AU - Hooning, Maartje J.

AU - Hollestelle, Antoinette

AU - Martens, John W M

AU - Collée, J. Margriet

AU - Hall, Per

AU - Li, Jingmei

AU - Humphreys, Keith

AU - Shu, Xiao Ou

AU - Lu, Wei

AU - Gao, Yu Tang

AU - Cai, Hui

AU - Cox, Angela

AU - Cross, Simon S.

AU - Reed, Malcolm W R

AU - Blot, William

AU - Signorello, Lisa B.

AU - Cai, Qiuyin

AU - Shah, Mitul

AU - Ghoussaini, Maya

AU - Kang, Daehee

AU - Choi, Ji Yeob

AU - Park, Sue K.

AU - Noh, Dong Young

AU - Hartman, Mikael

AU - Miao, Hui

AU - Lim, Wei Yen

AU - Tang, Anthony

AU - Hamann, Ute

AU - Torres, Diana

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Jaworska, Katarzyna

AU - Durda, Katarzyna

AU - Sangrajrang, Suleeporn

AU - Gaborieau, Valerie

AU - Brennan, Paul

AU - McKay, James

AU - Olswold, Curtis

AU - Slager, Susan

AU - Toland, Amanda E.

AU - Yannoukakos, Drakoulis

AU - Shen, Chen Yang

AU - Wu, Pei Ei

AU - Yu, Jyh Cherng

AU - Hou, Ming Feng

AU - Swerdlow, Anthony

AU - Ashworth, Alan

AU - Orr, Nick

AU - Jones, Michael

AU - Pita, Guillermo

AU - Alonso, M. Rosario

AU - Álvarez, Nuria

AU - Herrero, Daniel

AU - Tessier, Daniel C.

AU - Vincent, Daniel

AU - Bacot, Francois

AU - Luccarini, Craig

AU - Baynes, Caroline

AU - Ahmed, Shahana

AU - Healey, Catherine S.

AU - Brown, Melissa A.

AU - Ponder, Bruce A J

AU - Chenevix-Trench, Georgia

AU - Thompson, Deborah J.

AU - Edwards, Stacey L.

AU - Easton, Douglas F.

AU - Dunning, Alison M.

AU - French, Juliet D.

PY - 2015/1/8

Y1 - 2015/1/8

N2 - Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER+: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10-44) and estrogen-receptor-negative (ER-: OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10-4) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10-5]) and five variants composing iCHAV3 (lead rs11949391; ER+: OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10-4). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

AB - Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER+: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10-44) and estrogen-receptor-negative (ER-: OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10-4) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10-5]) and five variants composing iCHAV3 (lead rs11949391; ER+: OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10-4). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

UR - http://www.scopus.com/inward/record.url?scp=84920818376&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920818376&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2014.11.009

DO - 10.1016/j.ajhg.2014.11.009

M3 - Article

VL - 96

SP - 5

EP - 20

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -