Genome-wide association study of germline variants and breast cancer-specific mortality View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-03

AUTHORS

Maria Escala-Garcia, Qi Guo, Thilo Dörk, Sander Canisius, Renske Keeman, Joe Dennis, Jonathan Beesley, Julie Lecarpentier, Manjeet K. Bolla, Qin Wang, Jean Abraham, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Paul L. Auer, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Bram Boeckx, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Adam Brentnall, Louise Brinton, Per Broberg, Ian W. Brock, Sara Y. Brucker, Barbara Burwinkel, Carlos Caldas, Trinidad Caldés, Daniele Campa, Federico Canzian, Angel Carracedo, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Ting-Yuan David Cheng, Suet-Feung Chin, Christine L. Clarke, Emilie Cordina-Duverger, Fergus J. Couch, David G. Cox, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Janet A. Dunn, Alison M. Dunning, Lorraine Durcan, Miriam Dwek, Helena M. Earl, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Jonine Figueroa, Dieter Flesch-Janys, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Eva Galle, Susan M. Gapstur, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Angela George, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Susan Hankinson, Elaine F. Harkness, Patricia A. Harrington, Steven N. Hart, Jaana M. Hartikainen, Alexander Hein, Peter Hillemanns, Louise Hiller, Bernd Holleczek, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Wolfgang Janni, Esther M. John, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Michael J. Kerin, Sofia Khan, Elza Khusnutdinova, Johanna I. Kiiski, Cari M. Kitahara, Julia A. Knight, Yon-Dschun Ko, Linetta B. Koppert, Veli-Matti Kosma, Peter Kraft, Vessela N. Kristensen, Ute Krüger, Tabea Kühl, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Flavio Lejbkowicz, Lian Li, Annika Lindblom, Sara Lindström, Martha Linet, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jan Lubiński, Michael P. Lux, Robert J. MacInnis, Melanie Maierthaler, Tom Maishman, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Dimitrios Mavroudis, Catriona McLean, Alfons Meindl, Pooja Middha, Nicola Miller, Roger L. Milne, Fernando Moreno, Anna Marie Mulligan, Claire Mulot, Rami Nassir, Susan L. Neuhausen, William T. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Håkan Olsson, Nick Orr, V. Shane Pankratz, Tjoung-Won Park-Simon, Jose I. A. Perez, Clara Pérez-Barrios, Paolo Peterlongo, Christos Petridis, Mila Pinchev, Karoliona Prajzendanc, Ross Prentice, Nadege Presneau, Darya Prokofieva, Katri Pylkäs, Brigitte Rack, Paolo Radice, Dhanya Ramachandran, Gadi Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Rebecca Roylance, Emmanouil Saloustros, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Lukas Schwentner, Rodney J. Scott, Christopher Scott, Caroline Seynaeve, Mitul Shah, Jacques Simard, Ann Smeets, Christof Sohn, Melissa C. Southey, Anthony J. Swerdlow, Aline Talhouk, Rulla M. Tamimi, William J. Tapper, Manuel R. Teixeira, Maria Tengström, Mary Beth Terry, Kathrin Thöne, Rob A. E. M. Tollenaar, Ian Tomlinson, Diana Torres, Thérèse Truong, Constance Turman, Clare Turnbull, Hans-Ulrich Ulmer, Michael Untch, Celine Vachon, Christi J. van Asperen, Ans M. W. van den Ouweland, Elke M. van Veen, Camilla Wendt, Alice S. Whittemore, Walter Willett, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Yan Zhang, Douglas F. Easton, Peter A. Fasching, Heli Nevanlinna, Diana M. Eccles, Paul D. P. Pharoah, Marjanka K. Schmidt

ABSTRACT

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients. More... »

PAGES

647-657

Journal

TITLE

British Journal of Cancer

ISSUE

6

VOLUME

120

Author Affiliations

  • Antoni van Leeuwenhoek Hospital
  • University of Cambridge
  • Hannover Medical School
  • QIMR Berghofer Medical Research Institute
  • NIHR Cambridge Dementia Biomedical Research Unit
  • University of Toronto
  • University of California, Irvine
  • German Cancer Research Center
  • University of Wisconsin–Milwaukee
  • Centre for Biomedical Network Research on Rare Diseases
  • City Of Hope National Medical Center
  • Örebro University Hospital
  • KU Leuven
  • University of Copenhagen
  • European Institute of Oncology
  • Oslo University Hospital
  • Queen Mary University of London
  • National Cancer Institute
  • Lund University
  • University of Sheffield
  • University of Tübingen
  • Institute of Cancer Research
  • University of Pisa
  • King Abdulaziz University
  • American Cancer Society
  • University Cancer Center Hamburg
  • Roswell Park Cancer Institute
  • Cancer Research UK Cambridge Institute
  • University of Sydney
  • University of Paris-Sud
  • Mayo Clinic
  • Imperial College London
  • Karolinska Institute
  • Temple University Health System
  • Leiden University Medical Center
  • University of Warwick
  • University of Southampton
  • University of Westminster
  • Harvard University
  • Leipzig University
  • St Mary's Hospital
  • University of Edinburgh
  • University Medical Center Hamburg-Eppendorf
  • University of California, San Diego
  • Royal Marsden NHS Foundation Trust
  • University Hospital of Heraklion
  • Monash University
  • Lunenfeld-Tanenbaum Research Institute
  • University of Utah
  • Spanish National Cancer Research Centre
  • University of Cologne
  • University of Southern California
  • Manchester University NHS Foundation Trust
  • Kuopio University Hospital
  • Krebsregister Saarland
  • Erasmus University Medical Center
  • University of Melbourne
  • University of Manchester
  • University of Oxford
  • Stanford University
  • Tampere University Hospital
  • Pomeranian Medical University
  • National University of Ireland, Galway
  • Bashkir State University
  • University of Hawaii at Manoa
  • Carmel Medical Center
  • Tianjin Medical University Cancer Institute and Hospital
  • Fred Hutchinson Cancer Research Center
  • German Breast group
  • Alfred Hospital
  • Ludwig Maximilian University of Munich
  • Heidelberg University
  • University Health Network
  • French Institute of Health and Medical Research
  • University of California, Davis
  • Queen's University Belfast
  • University of New Mexico
  • Hospital Monte Naranco
  • Hospital Universitario Puerta de Hierro Majadahonda
  • King's College London
  • University of Oulu
  • University College London Hospitals NHS Foundation Trust
  • University Hospital of Larissa
  • Case Western Reserve University
  • University of Newcastle Australia
  • Centre Hospitalier Universitaire de Québec
  • Universitaire Ziekenhuizen Leuven
  • University of British Columbia
  • University of Porto
  • University of Eastern Finland
  • Columbia University
  • Pontifical Xavierian University
  • Brigham and Women's Hospital
  • University of California Los Angeles
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41416-019-0393-x

    DOI

    http://dx.doi.org/10.1038/s41416-019-0393-x

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1112225309

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30787463


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    77 schema:description BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
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