A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Maria Escala-Garcia, Jean Abraham, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Alan Ashworth, Paul L. Auer, Päivi Auvinen, Matthias W. Beckmann, Jonathan Beesley, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, William Blot, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Sara Y. Brucker, Barbara Burwinkel, Carlos Caldas, Federico Canzian, Jenny Chang-Claude, Stephen J. Chanock, Suet-Feung Chin, Christine L. Clarke, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Janet A. Dunn, Alison M. Dunning, Miriam Dwek, Helena M. Earl, Diana M. Eccles, A. Heather Eliassen, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Susan M. Gapstur, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Angela George, Graham G. Giles, David E. Goldgar, Anna González-Neira, Mervi Grip, Pascal Guénel, Qi Guo, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Patricia A. Harrington, Louise Hiller, Maartje J. Hooning, John L. Hopper, Anthony Howell, Chiun-Sheng Huang, Guanmengqian Huang, David J. Hunter, Anna Jakubowska, Esther M. John, Rudolf Kaaks, Pooja Middha Kapoor, Renske Keeman, Cari M. Kitahara, Linetta B. Koppert, Peter Kraft, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Flavio Lejbkowicz, Annika Lindblom, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Tabea Maurer, Dimitrios Mavroudis, Alfons Meindl, Roger L. Milne, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, William G. Newman, Andrew F. Olshan, Janet E. Olson, Håkan Olsson, Nick Orr, Paolo Peterlongo, Christos Petridis, Ross L. Prentice, Nadege Presneau, Kevin Punie, Dhanya Ramachandran, Gad Rennert, Atocha Romero, Mythily Sachchithananthan, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Lukas Schwentner, Christopher Scott, Jacques Simard, Christof Sohn, Melissa C. Southey, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Manuel R. Teixeira, Mary Beth Terry, Heather Thorne, Rob A. E. M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Clare Turnbull, Celine M. Vachon, Lizet E. Kolk, Qin Wang, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Argyrios Ziogas, Paul D. P. Pharoah, Per Hall, Lodewyk F. A. Wessels, Georgia Chenevix-Trench, Gary D. Bader, Thilo Dörk, Douglas F. Easton, Sander Canisius () and Marjanka K. Schmidt ()
Additional contact information
Maria Escala-Garcia: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Jean Abraham: University of Cambridge
Irene L. Andrulis: Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
Hoda Anton-Culver: University of California Irvine
Volker Arndt: German Cancer Research Center (DKFZ)
Alan Ashworth: University of California San Francisco
Paul L. Auer: Fred Hutchinson Cancer Research Center
Päivi Auvinen: Kuopio University Hospital
Matthias W. Beckmann: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg
Jonathan Beesley: QIMR Berghofer Medical Research Institute
Sabine Behrens: German Cancer Research Center (DKFZ)
Javier Benitez: Spanish National Cancer Research Centre (CNIO)
Marina Bermisheva: Ufa Scientific Center of Russian Academy of Sciences
Carl Blomqvist: Helsinki University Hospital, University of Helsinki
William Blot: Vanderbilt University School of Medicine
Natalia V. Bogdanova: Hannover Medical School
Stig E. Bojesen: Copenhagen University Hospital
Manjeet K. Bolla: University of Cambridge
Anne-Lise Børresen-Dale: Oslo University Hospital-Radiumhospitalet
Hiltrud Brauch: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Hermann Brenner: German Cancer Research Center (DKFZ)
Sara Y. Brucker: University of Tübingen
Barbara Burwinkel: German Cancer Research Center (DKFZ)
Carlos Caldas: University of Cambridge
Federico Canzian: German Cancer Research Center (DKFZ)
Jenny Chang-Claude: German Cancer Research Center (DKFZ)
Stephen J. Chanock: National Cancer Institute, National Institutes of Health
Suet-Feung Chin: University of Cambridge
Christine L. Clarke: University of Sydney
Fergus J. Couch: Mayo Clinic
Angela Cox: University of Sheffield
Simon S. Cross: University of Sheffield
Kamila Czene: Karolinska Institutet
Mary B. Daly: Fox Chase Cancer Center
Joe Dennis: University of Cambridge
Peter Devilee: Leiden University Medical Center
Janet A. Dunn: University of Warwick
Alison M. Dunning: University of Cambridge
Miriam Dwek: University of Westminster
Helena M. Earl: University of Cambridge NHS Foundation Hospitals
Diana M. Eccles: University of Southampton
A. Heather Eliassen: Harvard Medical School
Carolina Ellberg: Lund University
D. Gareth Evans: University of Manchester
Peter A. Fasching: University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg
Jonine Figueroa: National Cancer Institute, National Institutes of Health
Henrik Flyger: Copenhagen University Hospital
Manuela Gago-Dominguez: Complejo Hospitalario Universitario de Santiago, SERGAS
Susan M. Gapstur: American Cancer Society
Montserrat García-Closas: National Cancer Institute, National Institutes of Health
José A. García-Sáenz: Centro Investigación Biomédica en Red de Cáncer (CIBERONC)
Mia M. Gaudet: American Cancer Society
Angela George: The Institute of Cancer Research
Graham G. Giles: Cancer Council Victoria
David E. Goldgar: University of Utah School of Medicine
Anna González-Neira: Spanish National Cancer Research Centre (CNIO)
Mervi Grip: University of Oulu
Pascal Guénel: University Paris-Saclay, INSERM, University Paris-Sud
Qi Guo: University of Cambridge
Christopher A. Haiman: University of Southern California
Niclas Håkansson: Karolinska Institutet
Ute Hamann: German Cancer Research Center (DKFZ)
Patricia A. Harrington: University of Cambridge
Louise Hiller: University of Warwick
Maartje J. Hooning: Erasmus MC Cancer Institute
John L. Hopper: The University of Melbourne
Anthony Howell: University of Manchester
Chiun-Sheng Huang: National Taiwan University Hospital and National Taiwan University College of Medicine
Guanmengqian Huang: German Cancer Research Center (DKFZ)
David J. Hunter: Harvard T.H. Chan School of Public Health
Anna Jakubowska: Pomeranian Medical University
Esther M. John: Stanford Cancer Institute, Stanford University School of Medicine
Rudolf Kaaks: German Cancer Research Center (DKFZ)
Pooja Middha Kapoor: German Cancer Research Center (DKFZ)
Renske Keeman: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Cari M. Kitahara: National Cancer Institute
Linetta B. Koppert: Erasmus MC Cancer Institute
Peter Kraft: Harvard T.H. Chan School of Public Health
Vessela N. Kristensen: Oslo University Hospital-Radiumhospitalet
Diether Lambrechts: VIB, VIB Center for Cancer Biology
Loic Le Marchand: University of Hawaii Cancer Center
Flavio Lejbkowicz: Clalit National Cancer Control Center
Annika Lindblom: Karolinska Institutet
Jan Lubiński: Pomeranian Medical University
Arto Mannermaa: University of Eastern Finland
Mehdi Manoochehri: German Cancer Research Center (DKFZ)
Siranoush Manoukian: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT)
Sara Margolin: Sšdersjukhuset
Maria Elena Martinez: University of California San Diego
Tabea Maurer: University Medical Center Hamburg-Eppendorf
Dimitrios Mavroudis: University Hospital of Heraklion
Alfons Meindl: Ludwig Maximilian University of Munich
Roger L. Milne: Cancer Council Victoria
Anna Marie Mulligan: University of Toronto
Susan L. Neuhausen: Beckman Research Institute of City of Hope
Heli Nevanlinna: University of Helsinki
William G. Newman: University of Manchester
Andrew F. Olshan: University of North Carolina at Chapel Hill
Janet E. Olson: Mayo Clinic
Håkan Olsson: Lund University
Nick Orr: Queen’s University Belfast
Paolo Peterlongo: IFOM - the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology
Christos Petridis: King’s College London
Ross L. Prentice: Fred Hutchinson Cancer Research Center
Nadege Presneau: University of Westminster
Kevin Punie: Leuven Cancer Institute, University Hospitals Leuven
Dhanya Ramachandran: Hannover Medical School
Gad Rennert: Clalit National Cancer Control Center
Atocha Romero: Hospital Universitario Puerta de Hierro
Mythily Sachchithananthan: University of Sydney
Emmanouil Saloustros: University Hospital of Larissa
Elinor J. Sawyer: King’s College London
Rita K. Schmutzler: University Hospital of Cologne
Lukas Schwentner: University Hospital Ulm
Christopher Scott: Mayo Clinic
Jacques Simard: Centre Hospitalier Universitaire de Québec - Université Laval
Christof Sohn: University of Heidelberg
Melissa C. Southey: Monash University
Anthony J. Swerdlow: The Institute of Cancer Research
Rulla M. Tamimi: Harvard Medical School
William J. Tapper: University of Southampton
Manuel R. Teixeira: Portuguese Oncology Institute
Mary Beth Terry: Columbia University
Heather Thorne: Peter MacCallum Cancer Center
Rob A. E. M. Tollenaar: Leiden University Medical Center
Ian Tomlinson: University of Birmingham
Melissa A. Troester: University of North Carolina at Chapel Hill
Thérèse Truong: University Paris-Saclay, INSERM, University Paris-Sud
Clare Turnbull: The Institute of Cancer Research
Celine M. Vachon: Mayo Clinic
Lizet E. Kolk: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Qin Wang: University of Cambridge
Robert Winqvist: University of Oulu
Alicja Wolk: Karolinska Institutet
Xiaohong R. Yang: National Cancer Institute, National Institutes of Health
Argyrios Ziogas: University of California Irvine
Paul D. P. Pharoah: University of Cambridge
Per Hall: Karolinska Institutet
Lodewyk F. A. Wessels: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Georgia Chenevix-Trench: QIMR Berghofer Medical Research Institute
Gary D. Bader: University of Toronto
Thilo Dörk: Hannover Medical School
Douglas F. Easton: University of Cambridge
Sander Canisius: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital
Marjanka K. Schmidt: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.

Date: 2020
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DOI: 10.1038/s41467-019-14100-6

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