Fine-scale mapping of the 4q24 locus identifies & pr two Independent loci associated with breast cancer risk

Xingyi Guo, Jirong Long, Chenjie Zeng, Kyriaki Michailidou, Maya Ghoussaini, Manjeet K. Bolla, Qin Wang, Roger L. Milne, Xiao Ou Shu, Qiuyin Cai, Jonathan Beesley, Siddhartha P. Kar, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Matthias W. Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, William Blot, Natalia BogdanovaStig E. Bojesen, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Annegien Broekss, Thomas Bruning, Barbara Burwinkel, Hui Cai, Sander Canisius, Jenny Chang-Claude, Ji Yeob Choi, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Hatef Darabi, Peter Devilee, Arnaud Droit, Thilo Dork, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Florentia Fostira, Valerie Gaborieau, Montserrat García-Closas, Graham G. Giles, Mervi Grip, Pascal Guenel, Christopher A. Haiman, Ute Hamann, Mikael Hartman, Antoinette Hollestelle, John L. Hopper, Chia Ni Hsiung, Hidemi Ito, Anna Jakubowska, Nichola Johnson, Maria Kabisch, Daehee Kang, Sofia Khan, Julia A. Knight, Veli Matti Kosma, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Annika Lindblom, Artitaya Lophatananon, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Frederik Marme, Keitaro Matsuo, Catriona A. McLean, Alfons Meindl, Kenneth Muir, Susan L. Neuhausen, Heli Nevanlinna, Silje Nord, Janet E. Olson, Nick Orr, Paolo Peterlongo, Thomas Choudary Putti, Anja Rudolph, Suleeporn Sangrajrang, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Chen Yang Shen, Jiajun Shi, Martha J. Shrubsole, Melissa C. Southey, Anthony Swerdlow, Soo Hwang Teo, Bernard Thienpont, Amanda Ewart Toland, Robert A E M Tollenaar, Ian P M Tomlinson, Therese Truong, Chiu Chen Tseng, Ans Van Den Ouweland, Wanqing Wen, Robert Winqvist, Anna Wu, Cheng Har Yip, M. Pilar Zamora, Ying Zheng, Per Hall, Paul D P Pharoah, Jacques Simard, Georgia Chenevix-Trench, Alison M. Dunning, Douglas F. Easton, Wei Zheng, Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch, Antonis Antoniou, Lesley McGuffog, Ken Offit, Andrew Lee, Ed Dicks, Craig Luccarini, Daniel C. Tessier, Francois Bacot, Daniel Vincent, Sylvie La Boissière, Frederic Robidoux, Sune F. Nielsen, Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer, Maggie Angelakos, Judi Maskiell, Ellen Van Der Schoot, Emiel Rutgers, Senno Verhoef, Frans Hogervorst, Prat Boonyawongviroj, Pornthep Siriwanarungsan, Michael Schrauder, Matthias Rübner, Sonja Oeser, Silke Landrith, Eileen Williams, Elaine Ryder-Mills, Kara Sargus, Niall McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones, Christof Sohn, Andeas Schneeweiß, Peter Bugert, Núria Álvarez, Leslie Bernstein, James Lacey, Sophia Wang, Huiyan Ma, Yani Lu, Jessica Clague De Hart, Dennis Deapen, Rich Pinder, Eunjung Lee, Fred Schumacher, Pam Horn-Ross, Peggy Reynolds, David Nelson, Hannah Park, Hartwig Ziegler, Sonja Wolf, Volker Hermann, Wing Yee Lo, Christina Justenhoven, Yon Dschun Ko, Christian Baisch, Hans Peter Fischer, Beate Pesch, Sylvia Rabstein, Anne Lotz, Volker Harth, Tuomas Heikkinen, Irja Erkkilä, Kirsimari Aaltonen, Karl Von Smitten, Natalia Antonenkova, Peter Hillemanns, Hans Christiansen, Eija Myöhänen, Helena Kemiläinen, Heather Thorne, Eveline Niedermayr, D. Bowtell, G. Chenevix-Trench, A. De Fazio, D. Gertig, A. Green, P. Webb, A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman, Annie Fung, June Yashiki, Gilian Peuteman, Dominiek Smeets, Thomas Van Brussel, Kathleen Corthouts, Nadia Obi, Judith Heinz, Sabine Behrens, Ursula Eilber, Muhabbet Celik, Til Olchers, Bernard Peissel, Giulietta Scuvera, Daniela Zaffaroni, Bernardo Bonanni, Irene Feroce, Angela Maniscalco, Alessandra Rossi, Loris Bernard, Martine Tranchant, Marie France Valois, Annie Turgeon, Lea Heguy, Phuah Sze Yee, Peter Kang, Kang In Nee, Shivaani Mariapun, Yoon Sook-Yee, Daphne Lee, Teh Yew Ching, Nur Aishah Mohd Taib, Meeri Otsukka, Kari Mononen, Teresa Selander, Nayana Weerasooriya, E. Krol-Warmerdam, J. Molenaar, J. Blom, Neonila Szeszenia-Dabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner, Petra Bos, Jannet Blom, Ellen Crepin, Anja Nieuwlaat, Annette Heemskerk, Sue Higham, Helen Cramp, Dan Connley, Sabapathy Balasubramanian, Ian Brock, Michael Kerin, Nicola Miller, Pierre Kerbrat, Patrick Arveux, Romuald Le Scodan, Yves Raoul, Pierre Laurent-Puig, Claire Mulot, Christa Stegmaier, Katja Butterbach, Johann H. Karstens, Dieter Flesch-Janys, Petra Seibold, Alina Vrieling, Stefan Nickels, Paolo Radice, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Don Conroy, Caroline Baynes, Kimberley Chua, Robert Pilarski

Research output: Contribution to journalArticlepeer-review

Abstract

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P=2.51 × 10-4; OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P=1.86 × 10-4; OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.

Original languageEnglish
Pages (from-to)1680-1691
Number of pages12
JournalCancer Epidemiology Biomarkers and Prevention
Volume24
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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