Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Chenjie Zeng, Xingyi Guo, Jirong Long, Karoline Kuchenbaecker, Arnaud Droit, Kyriaki Michailidou, Maya Ghoussaini, Siddhartha Kar, Adam Freeman, John Hopper, Roger L. Milne, Manjeet K. Bolla, Qin Wang, Joe Dennis, Simona Agata, Shahana Ahmed, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. AntonenkovaAdalgeir Arason, Volker Arndt, Banu K. Arun, Brita Arver, Francois Bacot, Daniel Barrowdale, Caroline Baynes, Alicia Beeghly-Fadiel, Javier Benitez, Marina Bermisheva, Carl Blomqvist, William J. Blot, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Anne Lise Børresen-Dale, Judith S. Brand, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Annegien Broeks, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Jane Carpenter, Jenny Chang-Claude, Ji Yeob Choi, Kathleen Claes, Christine Clarke, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Miguel de la Hoya, Kim De Leeneer, Peter Devilee, Orland Diez, Susan M. Domchek, Michele Doody, Cecilia M. Dorfling, Thilo Dörk, Isabel Dos-Santos-Silva, Martine Dumont, Miriam Dwek, Bernd Dworniczak, Kathleen M. Egan, Ursula Eilber, Zakaria Einbeigi, Bent Ejlertsen, Steve Ellis, Debra Frost, Fiona Lalloo, Peter A. Fasching, Jonine D. Figueroa, Henrik Flyger, Michael Friedlander, Eitan Friedman, Gaetana Gambino, Yu Tang Gao, Judy E. Garber, Montse Garcia-Closas, Andrea Gehrig, Francesca Damiola, Fabienne Lesueur, Sylvie Mazoyer, Dominique Stoppa-Lyonnet, Graham G. Giles, Andrew K. Godwin, David Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guenel, Lothar Haeberle, Christopher A. Haiman, Emily Hallberg, Ute Hamann, Thomas v O Hansen, Steven Hart, Jaana M. Hartikainen, Mikael Hartman, Norhashimah Hassan, Sue Healey, Frans B. Hogervorst, S. Verhoef, Carolyn B. Hendricks, Peter Hillemanns, Antoinette Hollestelle, Peter J. Hulick, David J. Hunter, Evgeny Imyanitov, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Katarzyna Jaworska-Bieniek, Uffe Birk Jensen, Esther M. John, Charles Joly Beauparlant, Michael E. Jones, Maria Kabisch, Daehee Kang, Beth Y. Karlan, Saila Kauppila, Michael J. Kerin, Sofia Khan, Elza Khusnutdinova, Julia A. Knight, Irene Konstantopoulou, Peter Kraft, A. Kwong, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Loic Le Marchand, Chuen Neng Lee, Min Hyuk Lee, Jenny Lester, Jingmei Li, Annelie Liljegren, Annika Lindblom, Artitaya Lophatananon, Jan Lubinski, Phuong L. Mai, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Frederik Marme, Keitaro Matsuo, Lesley McGuffog, Alfons Meindl, Florence Menegaux, Marco Montagna, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, P. Newcomb, Silje Nord, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Curtis Olswold, Ana Osorio, Laura Papi, Tjoung Won Park-Simon, Ylva Paulsson-Karlsson, Stephanie Peeters, Bernard Gilles Peissel, Paolo Peterlongo, Julian Peto, Georg Pfeiler, Catherine M. Phelan, Nadege Presneau, Paolo Radice, Nazneen Rahman, Susan J. Ramus, Muhammad Usman Rashid, Gad Rennert, Kerstin Rhiem, Anja Rudolph, Ritu Salani, Suleeporn Sangrajrang, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Minouk J. Schoemaker, Peter Schürmann, Caroline Seynaeve, Chen Yang Shen, Martha Shrubsole, Xiao Ou Shu, Alice J. Sigurdson, Christian F. Singer, Susan Slager, Penny Soucy, Melissa Southey, Doris Steinemann, Anthony J. Swerdlow, Csilla I. Szabo, Sandrine Tchatchou, Manuel R. Teixeira, Soo Hwang Teo, Mary Beth Terry, Daniel C. Tessier, A. Teulé, Mads Thomassen, Laima Tihomirova, Marc Tischkowitz, Amanda E. Toland, Nadine Tung, Clare Turnbull, Ans M W Van Den Ouweland, Elizabeth J. van Rensburg, David ven den Berg, Joseph Vijai, Shan Wang-Gohrke, Jeffrey Weitzel, Alice S. Whittemore, Robert Winqvist, Tien Y. Wong, Anna H. Wu, Drakoulis Yannoukakos, Jyh Cherng Yu, Paul D P Pharoah, Per Hall, Georgia Chenevix-Trench, Alison Dunning, Jacques Simard, Fergus J. Couch, Antonis C. Antoniou, Douglas F. Easton, Wei Zheng

Research output: Contribution to journalArticle

Abstract

Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P <0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P <0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.

Original languageEnglish
Article number64
JournalBreast Cancer Research
Volume18
Issue number1
DOIs
Publication statusPublished - Jun 21 2016

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Keywords

  • BRAC1 mutation carriers
  • Breast cancer
  • CCDC91
  • Fine-scale mapping
  • Genetic risk factor
  • PTHLH

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zeng, C., Guo, X., Long, J., Kuchenbaecker, K., Droit, A., Michailidou, K., Ghoussaini, M., Kar, S., Freeman, A., Hopper, J., Milne, R. L., Bolla, M. K., Wang, Q., Dennis, J., Agata, S., Ahmed, S., Aittomäki, K., Andrulis, I. L., Anton-Culver, H., ... Zheng, W. (2016). Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus. Breast Cancer Research, 18(1), [64]. https://doi.org/10.1186/s13058-016-0718-0