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. HogervorstC. 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
Pages (from-to)5-20
Number of pages16
JournalAmerican Journal of Human Genetics
Volume96
Issue number1
DOIs
Publication statusPublished - Jan 8 2015

    Fingerprint

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Glubb, D. M., Maranian, M. J., Michailidou, K., Pooley, K. A., Meyer, K. B., Kar, S., Carlebur, S., O'Reilly, M., Betts, J. A., Hillman, K. M., Kaufmann, S., Beesley, J., Canisius, S., Hopper, J. L., Southey, M. C., Tsimiklis, H., Apicella, C., Schmidt, M. K., Broeks, A., ... French, J. D. (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, 96(1), 5-20. https://doi.org/10.1016/j.ajhg.2014.11.009