Format

Send to

Choose Destination
Nat Commun. 2020 Jan 16;11(1):312. doi: 10.1038/s41467-019-14100-6.

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

Escala-Garcia M1, Abraham J2,3,4, Andrulis IL5,6, Anton-Culver H7, Arndt V8, Ashworth A9, Auer PL10,11, Auvinen P12,13,14, Beckmann MW15, Beesley J16, Behrens S17, Benitez J18,19, Bermisheva M20, Blomqvist C21,22, Blot W23,24, Bogdanova NV25,26,27, Bojesen SE28,29,30, Bolla MK31, Børresen-Dale AL32,33, Brauch H34,35,36, Brenner H8,36,37, Brucker SY38, Burwinkel B39,40, Caldas C41,42, Canzian F43, Chang-Claude J17,44, Chanock SJ45, Chin SF46, Clarke CL47, Couch FJ48, Cox A49, Cross SS50, Czene K51, Daly MB52, Dennis J31, Devilee P53,54, Dunn JA55, Dunning AM2, Dwek M56, Earl HM4,57, Eccles DM58, Eliassen AH59,60, Ellberg C61, Evans DG62,63,64, Fasching PA15,65, Figueroa J45,66,67, Flyger H68, Gago-Dominguez M69,70, Gapstur SM71, García-Closas M45,72, García-Sáenz JA73, Gaudet MM71, George A74, Giles GG75,76,77, Goldgar DE78, González-Neira A18, Grip M79, Guénel P80, Guo Q81, Haiman CA82, Håkansson N83, Hamann U84, Harrington PA2, Hiller L55, Hooning MJ85, Hopper JL76, Howell A86, Huang CS87, Huang G84, Hunter DJ60,88,89, Jakubowska A90,91, John EM92, Kaaks R17, Kapoor PM17,93, Keeman R1, Kitahara CM94, Koppert LB95, Kraft P60,88, Kristensen VN32,33, Lambrechts D96,97, Le Marchand L98, Lejbkowicz F99, Lindblom A100,101, Lubiński J90, Mannermaa A14,102,103, Manoochehri M84, Manoukian S104, Margolin S105,106, Martinez ME70,107, Maurer T44, Mavroudis D108, Meindl A109, Milne RL75,76,110, Mulligan AM111,112, Neuhausen SL113, Nevanlinna H114, Newman WG62,63, Olshan AF115, Olson JE116, Olsson H61, Orr N117, Peterlongo P118, Petridis C119, Prentice RL10, Presneau N56, Punie K120, Ramachandran D26, Rennert G99, Romero A121, Sachchithananthan M47, Saloustros E122, Sawyer EJ119, Schmutzler RK123,124, Schwentner L125, Scott C116, Simard J126, Sohn C127, Southey MC110,128, Swerdlow AJ74,129, Tamimi RM59,60,88, Tapper WJ130, Teixeira MR131,132, Terry MB133, Thorne H134,135, Tollenaar RAEM136, Tomlinson I137,138, Troester MA115, Truong T80, Turnbull C74, Vachon CM116, van der Kolk LE139, Wang Q31, Winqvist R140,141, Wolk A83,142, Yang XR45, Ziogas A7, Pharoah PDP2,31, Hall P51,105, Wessels LFA143,144, Chenevix-Trench G16, Bader GD6,145, Dörk T26, Easton DF2,31, Canisius S146,147, Schmidt MK148,149.

Author information

1
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
2
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
3
Cambridge Experimental Cancer Medicine Centre, Cambridge, UK.
4
Cambridge Breast Unit and NIHR Cambridge Biomedical Research Centre, University of Cambridge NHS Foundation Hospitals, Cambridge, UK.
5
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
6
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
7
Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
8
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
9
UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
10
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
11
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
12
Cancer Center, Kuopio University Hospital, Kuopio, Finland.
13
Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland.
14
Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
15
Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
16
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
17
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
18
Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
19
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
20
Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia.
21
Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
22
Department of Oncology, Örebro University Hospital, Örebro, Sweden.
23
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
24
International Epidemiology Institute, Rockville, MD, USA.
25
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
26
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
27
N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
28
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
29
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
30
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
31
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
32
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
33
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
34
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
35
iFIT-Cluster of Excellence, University of Tuebingen, Tuebingen, Germany.
36
German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
37
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
38
Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
39
Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
40
Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
41
Cancer Research UK Cambridge Institute, Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
42
Breast Cancer Programme, CRUK Cambridge Cancer Centre and NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
43
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
44
Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
45
Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
46
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
47
Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.
48
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
49
Department of Oncology and Metabolism, Sheffield Institute for Nucleic Acids (SInFoNiA), University of Sheffield, Sheffield, UK.
50
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
51
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
52
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
53
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
54
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
55
Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.
56
Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK.
57
Department of Oncology, University of Cambridge, Cambridge, UK.
58
Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
59
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
60
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
61
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
62
Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
63
Genomic Medicine, St Mary's Hospital, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
64
NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
65
Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
66
Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
67
Cancer Research UK Edinburgh Centre, Edinburgh, UK.
68
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
69
Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
70
Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
71
Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
72
Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
73
Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
74
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
75
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
76
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
77
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
78
Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
79
Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
80
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), University Paris-Saclay, INSERM, University Paris-Sud, Villejuif, France.
81
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
82
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
83
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
84
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
85
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
86
Division of Cancer Sciences, University of Manchester, Manchester, UK.
87
Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
88
Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
89
Nuffield Department of Population Health, University of Oxford, Oxford, UK.
90
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
91
Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
92
Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
93
Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.
94
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
95
Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
96
VIB, VIB Center for Cancer Biology, Leuven, Belgium.
97
Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
98
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
99
Carmel Medical Center and Technion Faculty of Medicine, Clalit National Cancer Control Center, Haifa, Israel.
100
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
101
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
102
Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.
103
Department of Clinical Pathology, Imaging Center, Kuopio University Hospital, Kuopio, Finland.
104
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT), Milan, Italy.
105
Department of Oncology, Sšdersjukhuset, Stockholm, Sweden.
106
Department of Clinical Science and Education, Sšdersjukhuset, Karolinska Institutet, Stockholm, Sweden.
107
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
108
Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
109
Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany.
110
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia.
111
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
112
Laboratory Medicine Program, University Health Network, Toronto, ON, Canada.
113
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
114
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
115
Department of Epidemiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
116
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
117
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Ireland, UK.
118
Genome Diagnostics Program, IFOM - the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
119
Research Oncology, Guy's Hospital, King's College London, London, UK.
120
Department of Oncology, Leuven Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
121
Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
122
Department of Oncology, University Hospital of Larissa, Larissa, Greece.
123
Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
124
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
125
Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
126
Genomics Center, Research Center, Centre Hospitalier Universitaire de Québec - Université Laval, Québec City, QC, Canada.
127
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
128
Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
129
Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
130
Faculty of Medicine, University of Southampton, Southampton, UK.
131
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
132
Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
133
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
134
Peter MacCallum Cancer Center, Melbourne, VIC, Australia.
135
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
136
Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
137
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
138
Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
139
Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
140
Biocenter Oulu, Cancer and Translational Medicine Research Unit, Laboratory of Cancer Genetics and Tumor Biology, University of Oulu, Oulu, Finland.
141
Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.
142
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
143
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
144
Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands.
145
The Donnelly Centre, University of Toronto, Toronto, ON, Canada.
146
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. s.canisius@nki.nl.
147
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. s.canisius@nki.nl.
148
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. mk.schmidt@nki.nl.
149
Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. mk.schmidt@nki.nl.

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.

Grant support

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central Icon for Norwegian BIBSYS system
Loading ...
Support Center