| Literature DB >> 25529635 |
Dylan M Glubb1, Mel J Maranian2, Kyriaki Michailidou3, Karen A Pooley2, Kerstin B Meyer4, Siddhartha Kar3, Saskia Carlebur4, Martin O'Reilly4, Joshua A Betts5, Kristine M Hillman1, Susanne Kaufmann1, Jonathan Beesley1, Sander Canisius6, John L Hopper7, Melissa C Southey8, Helen Tsimiklis8, Carmel Apicella8, Marjanka K Schmidt6, Annegien Broeks6, Frans B Hogervorst6, C Ellen van der Schoot9, Kenneth Muir10, Artitaya Lophatananon11, Sarah Stewart-Brown11, Pornthep Siriwanarangsan12, Peter A Fasching13, Matthias Ruebner14, Arif B Ekici15, Matthias W Beckmann14, Julian Peto16, Isabel dos-Santos-Silva16, Olivia Fletcher17, Nichola Johnson17, Paul D P Pharoah18, Manjeet K Bolla3, Qin Wang3, Joe Dennis3, Elinor J Sawyer19, Ian Tomlinson20, Michael J Kerin21, Nicola Miller21, Barbara Burwinkel22, Frederik Marme23, Rongxi Yang24, Harald Surowy24, Pascal Guénel25, Thérèse Truong25, Florence Menegaux25, Marie Sanchez25, Stig E Bojesen26, Børge G Nordestgaard26, Sune F Nielsen27, Henrik Flyger28, Anna González-Neira29, Javier Benitez30, M Pilar Zamora31, Jose Ignacio Arias Perez32, Hoda Anton-Culver33, Susan L Neuhausen34, Hermann Brenner35, Aida Karina Dieffenbach35, Volker Arndt36, Christa Stegmaier37, Alfons Meindl38, Rita K Schmutzler39, Hiltrud Brauch40, Yon-Dschun Ko41, Thomas Brüning42, Heli Nevanlinna43, Taru A Muranen43, Kristiina Aittomäki44, Carl Blomqvist45, Keitaro Matsuo46, Hidemi Ito47, Hiroji Iwata48, Hideo Tanaka47, Thilo Dörk49, Natalia V Bogdanova50, Sonja Helbig49, Annika Lindblom51, Sara Margolin52, Arto Mannermaa53, Vesa Kataja54, Veli-Matti Kosma53, Jaana M Hartikainen53, Anna H Wu55, Chiu-chen Tseng55, David Van Den Berg55, Daniel O Stram55, Diether Lambrechts56, Hui Zhao56, Caroline Weltens57, Erik van Limbergen57, Jenny Chang-Claude58, Dieter Flesch-Janys59, Anja Rudolph58, Petra Seibold58, Paolo Radice60, Paolo Peterlongo61, Monica Barile62, Fabio Capra63, Fergus J Couch64, Janet E Olson65, Emily Hallberg65, Celine Vachon65, Graham G Giles66, Roger L Milne66, Catriona McLean67, Christopher A Haiman55, Brian E Henderson55, Fredrick Schumacher55, Loic Le Marchand68, Jacques Simard69, Mark S Goldberg70, France Labrèche71, Martine Dumont69, Soo Hwang Teo72, Cheng Har Yip73, Mee-Hoong See73, Belinda Cornes74, Ching-Yu Cheng74, M Kamran Ikram74, Vessela Kristensen75, Wei Zheng76, Sandra L Halverson76, Martha Shrubsole76, Jirong Long76, Robert Winqvist77, Katri Pylkäs77, Arja Jukkola-Vuorinen78, Saila Kauppila79, Irene L Andrulis80, Julia A Knight81, Gord Glendon82, Sandrine Tchatchou82, Peter Devilee83, Robert A E M Tollenaar83, Caroline Seynaeve84, Christi J Van Asperen85, Montserrat García-Closas86, Jonine Figueroa87, Stephen J Chanock87, Jolanta Lissowska88, Kamila Czene89, Daniel Klevebring89, Hatef Darabi89, Mikael Eriksson89, Maartje J Hooning90, Antoinette Hollestelle90, John W M Martens90, J Margriet Collée91, Per Hall89, Jingmei Li92, Keith Humphreys89, Xiao-Ou Shu76, Wei Lu93, Yu-Tang Gao94, Hui Cai76, Angela Cox95, Simon S Cross96, Malcolm W R Reed95, William Blot97, Lisa B Signorello97, Qiuyin Cai76, Mitul Shah2, Maya Ghoussaini2, Daehee Kang98, Ji-Yeob Choi99, Sue K Park98, Dong-Young Noh100, Mikael Hartman101, Hui Miao102, Wei Yen Lim102, Anthony Tang103, Ute Hamann104, Diana Torres105, Anna Jakubowska106, Jan Lubinski106, Katarzyna Jaworska106, Katarzyna Durda106, Suleeporn Sangrajrang107, Valerie Gaborieau108, Paul Brennan108, James McKay108, Curtis Olswold65, Susan Slager65, Amanda E Toland109, Drakoulis Yannoukakos110, Chen-Yang Shen111, Pei-Ei Wu112, Jyh-Cherng Yu113, Ming-Feng Hou114, Anthony Swerdlow115, Alan Ashworth17, Nick Orr17, Michael Jones116, Guillermo Pita29, M Rosario Alonso29, Nuria Álvarez29, Daniel Herrero29, Daniel C Tessier117, Daniel Vincent117, Francois Bacot117, Craig Luccarini2, Caroline Baynes2, Shahana Ahmed2, Catherine S Healey2, Melissa A Brown118, Bruce A J Ponder4, Georgia Chenevix-Trench1, Deborah J Thompson3, Stacey L Edwards5, Douglas F Easton18, Alison M Dunning119, Juliet D French120.
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.Entities:
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Year: 2014 PMID： 25529635 PMCID： PMC4289692 DOI： 10.1016/j.ajhg.2014.11.009
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025