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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-12

AUTHORS

Chenjie Zeng, Xingyi Guo, Jirong Long, Karoline B. Kuchenbaecker, Arnaud Droit, Kyriaki Michailidou, Maya Ghoussaini, Siddhartha Kar, Adam Freeman, John L. 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. Antonenkova, Adalgeir 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 Borresen-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 B. M. 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 Egan, Ursula Eilber, Zakaria Einbeigi, Bent Ejlertsen, Steve Ellis, Debra Frost, Fiona Lalloo, on behalf of EMBRACE, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Michael Friedlander, Eitan Friedman, Gaetana Gambino, Yu-Tang Gao, Judy Garber, Montserrat García-Closas, Andrea Gehrig, Francesca Damiola, Fabienne Lesueur, Sylvie Mazoyer, Dominique Stoppa-Lyonnet, behalf of GEMO Study Collaborators, Graham G. Giles, Andrew K. Godwin, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, 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. L. Hogervorst, Senno Verhoef, on behalf of HEBON, Carolyn B. Hendricks, Peter Hillemanns, Antoinette Hollestelle, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Katarzyna Jaworska-Bieniek, Uffe Birk Jensen, Esther M. John, Charles Joly Beauparlant, Michael Jones, Maria Kabisch, Daehee Kang, Beth Y. Karlan, Saila Kauppila, Michael J. Kerin, Sofia Khan, Elza Khusnutdinova, Julia A. Knight, Irene Konstantopoulou, Peter Kraft, Ava 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, Polly A. 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 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 J. Shrubsole, Xiao-Ou Shu, Alice Sigurdson, Christian F. Singer, Susan Slager, Penny Soucy, Melissa Southey, Doris Steinemann, Anthony Swerdlow, Csilla I. Szabo, Sandrine Tchatchou, Manuel R. Teixeira, Soo H. Teo, Mary Beth Terry, Daniel C. Tessier, Alex 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 N. 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, on behalf of KConFab, AOCS Investigators, Alison M. Dunning, Jacques Simard, Fergus J. Couch, Antonis C. Antoniou, Douglas F. Easton, Wei Zheng

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. More... »

PAGES

64

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  • Journal

    TITLE

    Breast Cancer Research

    ISSUE

    1

    VOLUME

    18

    Author Affiliations

  • University of Cambridge
  • Université Laval
  • St Vincent's Hospital
  • University of Melbourne
  • Cancer Council Victoria
  • Istituti di Ricovero e Cura a Carattere Scientifico
  • University of Toronto
  • University of California, Irvine
  • University of Iceland
  • German Cancer Research Center
  • The University of Texas MD Anderson Cancer Center
  • Karolinska University Hospital
  • McGill University and Génome Québec Innovation Centre
  • Spanish National Cancer Research Centre
  • Institute of Biochemistry and Genetics of Ufa Scientific Centre
  • International Epidemiology Institute
  • Hannover Medical School
  • University of Copenhagen
  • European Institute of Oncology
  • Oslo University Hospital
  • Karolinska Institute
  • International Agency For Research On Cancer
  • Antoni van Leeuwenhoek Hospital
  • Ruhr University Bochum
  • University of Utah
  • Hospital Clínico San Carlos
  • Peter MacCallum Cancer Centre
  • University of Sydney
  • University Cancer Center Hamburg
  • Seoul National University
  • Ghent University
  • University of Sheffield
  • Temple University Health System
  • Leiden University Medical Center
  • Hospital Universitari Vall d'Hebron
  • University of Pennsylvania
  • National Cancer Institute
  • University of Pretoria
  • London School of Hygiene & Tropical Medicine
  • University of Westminster
  • University of Bonn
  • Moffitt Cancer Center
  • Sahlgrenska University Hospital
  • Manchester University NHS Foundation Trust
  • University of California Los Angeles
  • Herlev Hospital
  • Sheba Medical Center
  • Azienda Ospedaliera Universitaria Pisana
  • Shanghai Cancer Institute
  • Dana–Farber Cancer Institute
  • Institute of Cancer Research
  • University of Würzburg
  • University of Lyon System
  • Paris Descartes University
  • University of Kansas Medical Center
  • University of Paris-Sud
  • University of Southern California
  • Mayo Clinic
  • Kuopio University Hospital
  • National University Health System
  • University Malaya Medical Centre
  • QIMR Berghofer Medical Research Institute
  • Suburban Hospital
  • Erasmus University Medical Center
  • NorthShore University HealthSystem
  • Harvard University
  • Institute of Oncology NN Petrov
  • Georgetown University Medical Center
  • Aichi Cancer Center
  • Pomeranian Medical University
  • State Research Institute Centre for Innovative Medicine
  • Aarhus University Hospital
  • Stanford University
  • Cedars-Sinai Medical Center
  • National University of Ireland, Galway
  • Bashkir State University
  • National Centre of Scientific Research Demokritos
  • University of Hong Kong
  • KU Leuven
  • University of Hawaii at Manoa
  • National University of Singapore
  • Soonchunhyang University Hospital
  • University of Warwick
  • Istituto Nazionale dei Tumori
  • Heidelberg University
  • Kyushu University
  • Technical University Munich
  • University of Manchester
  • City Of Hope National Medical Center
  • Fred Hutchinson Cancer Research Center
  • University of California, San Francisco
  • Memorial Sloan Kettering Cancer Center
  • National Institute of Oncology
  • University of Chicago Medical Center
  • Centre for Biomedical Network Research on Rare Diseases
  • University of Florence
  • Uppsala University
  • Universitaire Ziekenhuizen Leuven
  • Medical University of Vienna
  • Shaukat Khanum Memorial Cancer Hospital and Research Center
  • Technion – Israel Institute of Technology
  • University Hospital Cologne
  • The Ohio State University
  • National Cancer Institute of Thailand
  • King's College London
  • Academia Sinica
  • Centre Hospitalier Universitaire de Québec
  • National Human Genome Research Institute
  • Lunenfeld-Tanenbaum Research Institute
  • University of Porto
  • Columbia University
  • Odense University Hospital
  • Latvian Biomedical Research and Study Centre
  • Beth Israel Deaconess Medical Center
  • University of Ulm
  • University of Oulu
  • Aristotle University of Thessaloniki
  • National Taiwan University Hospital
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s13058-016-0718-0

    DOI

    http://dx.doi.org/10.1186/s13058-016-0718-0

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1052669138

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/27459855


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    76 schema:description 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.
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