Scientific Reports (Oct 2021)
Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis
- Maria Escala-Garcia,
- Sander Canisius,
- Renske Keeman,
- Jonathan Beesley,
- Hoda Anton-Culver,
- Volker Arndt,
- Annelie Augustinsson,
- Heiko Becher,
- Matthias W. Beckmann,
- Sabine Behrens,
- Marina Bermisheva,
- Stig E. Bojesen,
- Manjeet K. Bolla,
- Hermann Brenner,
- Federico Canzian,
- Jose E. Castelao,
- Jenny Chang-Claude,
- Stephen J. Chanock,
- Fergus J. Couch,
- Kamila Czene,
- Mary B. Daly,
- Joe Dennis,
- Peter Devilee,
- Thilo Dörk,
- Alison M. Dunning,
- Douglas F. Easton,
- Arif B. Ekici,
- A. Heather Eliassen,
- Peter A. Fasching,
- Henrik Flyger,
- Manuela Gago-Dominguez,
- Montserrat García-Closas,
- José A. García-Sáenz,
- Jürgen Geisler,
- Graham G. Giles,
- Mervi Grip,
- Melanie Gündert,
- Eric Hahnen,
- Christopher A. Haiman,
- Niclas Håkansson,
- Per Hall,
- Ute Hamann,
- Jaana M. Hartikainen,
- Bernadette A. M. Heemskerk-Gerritsen,
- Antoinette Hollestelle,
- Reiner Hoppe,
- John L. Hopper,
- David J. Hunter,
- William Jacot,
- Anna Jakubowska,
- Esther M. John,
- Audrey Y. Jung,
- Rudolf Kaaks,
- Elza Khusnutdinova,
- Linetta B. Koppert,
- Peter Kraft,
- Vessela N. Kristensen,
- Allison W. Kurian,
- Diether Lambrechts,
- Loic Le Marchand,
- Annika Lindblom,
- Robert N. Luben,
- Jan Lubiński,
- Arto Mannermaa,
- Mehdi Manoochehri,
- Sara Margolin,
- Dimitrios Mavroudis,
- Taru A. Muranen,
- Heli Nevanlinna,
- Andrew F. Olshan,
- Håkan Olsson,
- Tjoung-Won Park-Simon,
- Alpa V. Patel,
- Paolo Peterlongo,
- Paul D. P. Pharoah,
- Kevin Punie,
- Paolo Radice,
- Gad Rennert,
- Hedy S. Rennert,
- Atocha Romero,
- Rebecca Roylance,
- Thomas Rüdiger,
- Matthias Ruebner,
- Emmanouil Saloustros,
- Elinor J. Sawyer,
- Rita K. Schmutzler,
- Minouk J. Schoemaker,
- Christopher Scott,
- Melissa C. Southey,
- Harald Surowy,
- Anthony J. Swerdlow,
- Rulla M. Tamimi,
- Lauren R. Teras,
- Emilie Thomas,
- Ian Tomlinson,
- Melissa A. Troester,
- Celine M. Vachon,
- Qin Wang,
- Robert Winqvist,
- Alicja Wolk,
- Argyrios Ziogas,
- kConFab/AOCS Investigators,
- Kyriaki Michailidou,
- Georgia Chenevix-Trench,
- Thomas Bachelot,
- Marjanka K. Schmidt
Affiliations
- Maria Escala-Garcia
- Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital
- Sander Canisius
- Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital
- Renske Keeman
- Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital
- Jonathan Beesley
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute
- Hoda Anton-Culver
- Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine
- Volker Arndt
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)
- Annelie Augustinsson
- Department of Cancer Epidemiology, Clinical Sciences, Lund University
- Heiko Becher
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf
- Matthias W. Beckmann
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU)
- Sabine Behrens
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ)
- Marina Bermisheva
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences
- Stig E. Bojesen
- Copenhagen University Hospital, Copenhagen General Population Study
- Manjeet K. Bolla
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge
- Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ)
- Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ)
- Jose E. Castelao
- Instituto de Investigación Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Oncology and Genetics Unit
- Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ)
- Stephen J. Chanock
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health
- Fergus J. Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic
- Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Mary B. Daly
- Department of Clinical Genetics, Fox Chase Cancer Center
- Joe Dennis
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge
- Peter Devilee
- Department of Pathology, Leiden University Medical Center
- Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School
- Alison M. Dunning
- Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge
- Douglas F. Easton
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge
- Arif B. Ekici
- Institute of Human Genetics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU)
- A. Heather Eliassen
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
- Peter A. Fasching
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU)
- Henrik Flyger
- Department of Breast Surgery, Copenhagen University Hospital
- Manuela Gago-Dominguez
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Fundación Pública Galega de Medicina Xenómica
- Montserrat García-Closas
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health
- José A. García-Sáenz
- Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Medical Oncology Department, Hospital Clínico San Carlos
- Jürgen Geisler
- Department of Oncology, Akershus University Hospital
- Graham G. Giles
- Cancer Council Victoria, Cancer Epidemiology Division
- Mervi Grip
- Department of Surgery, Oulu University Hospital, University of Oulu
- Melanie Gündert
- German Cancer Research Center (DKFZ), Molecular Epidemiology Group, C080
- Eric Hahnen
- Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne
- Christopher A. Haiman
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California
- Niclas Håkansson
- Institute of Environmental Medicine, Karolinska Institutet
- Per Hall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Ute Hamann
- German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer
- Jaana M. Hartikainen
- Translational Cancer Research Area, University of Eastern Finland
- Bernadette A. M. Heemskerk-Gerritsen
- Department of Medical Oncology, Erasmus MC Cancer Institute
- Antoinette Hollestelle
- Department of Medical Oncology, Erasmus MC Cancer Institute
- Reiner Hoppe
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
- John L. Hopper
- Melbourne School of Population and Global Health, Centre for Epidemiology and Biostatistics, The University of Melbourne
- David J. Hunter
- Department of Epidemiology, Harvard T.H. Chan School of Public Health
- William Jacot
- Institut du Cancer de Montpellier, Montpellier University
- Anna Jakubowska
- Department of Genetics and Pathology, Pomeranian Medical University
- Esther M. John
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford Cancer Institute
- Audrey Y. Jung
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ)
- Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ)
- Elza Khusnutdinova
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences
- Linetta B. Koppert
- Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute
- Peter Kraft
- Department of Epidemiology, Harvard T.H. Chan School of Public Health
- Vessela N. Kristensen
- Department of Medical Genetics, Oslo University Hospital and University of Oslo
- Allison W. Kurian
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford Cancer Institute
- Diether Lambrechts
- VIB Center for Cancer Biology
- Loic Le Marchand
- University of Hawaii Cancer Center, Epidemiology Program
- Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet
- Robert N. Luben
- NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology
- Jan Lubiński
- Department of Genetics and Pathology, Pomeranian Medical University
- Arto Mannermaa
- Translational Cancer Research Area, University of Eastern Finland
- Mehdi Manoochehri
- German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer
- Sara Margolin
- Department of Oncology, Sšdersjukhuset
- Dimitrios Mavroudis
- Department of Medical Oncology, University Hospital of Heraklion
- Taru A. Muranen
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki
- Heli Nevanlinna
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki
- Andrew F. Olshan
- Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
- Håkan Olsson
- Department of Cancer Epidemiology, Clinical Sciences, Lund University
- Tjoung-Won Park-Simon
- Gynaecology Research Unit, Hannover Medical School
- Alpa V. Patel
- Department of Population Science, American Cancer Society
- Paolo Peterlongo
- IFOM-The FIRC Institute of Molecular Oncology, Genome Diagnostics Program
- Paul D. P. Pharoah
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge
- Kevin Punie
- Department of General Medical Oncology and Multidisciplinary Breast Centre, Leuven Cancer Institute, University Hospitals Leuven
- Paolo Radice
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT)
- Gad Rennert
- Carmel Medical Center and Technion Faculty of Medicine, Clalit National Cancer Control Center
- Hedy S. Rennert
- Carmel Medical Center and Technion Faculty of Medicine, Clalit National Cancer Control Center
- Atocha Romero
- Medical Oncology Department, Hospital Universitario Puerta de Hierro
- Rebecca Roylance
- Department of Oncology, UCLH Foundation Trust
- Thomas Rüdiger
- Institute of Pathology, Staedtisches Klinikum Karlsruhe
- Matthias Ruebner
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU)
- Emmanouil Saloustros
- Department of Oncology, University Hospital of Larissa
- Elinor J. Sawyer
- School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, King’s College London
- Rita K. Schmutzler
- Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne
- Minouk J. Schoemaker
- Division of Genetics and Epidemiology, The Institute of Cancer Research
- Christopher Scott
- Department of Health Sciences Research, Mayo Clinic
- Melissa C. Southey
- Cancer Council Victoria, Cancer Epidemiology Division
- Harald Surowy
- German Cancer Research Center (DKFZ), Molecular Epidemiology Group, C080
- Anthony J. Swerdlow
- Division of Genetics and Epidemiology, The Institute of Cancer Research
- Rulla M. Tamimi
- Department of Epidemiology, Harvard T.H. Chan School of Public Health
- Lauren R. Teras
- Department of Population Science, American Cancer Society
- Emilie Thomas
- Plateforme de Bioinformatique Gilles Thomas, Centre de recherche en cancérologie de Lyon, Fondation Synergie Lyon Cancer, Université Claude Bernard Lyon 1
- Ian Tomlinson
- Institute of Cancer and Genomic Sciences, University of Birmingham
- Melissa A. Troester
- Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
- Celine M. Vachon
- Division of Epidemiology, Department of Health Science Research, Mayo Clinic
- Qin Wang
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge
- Robert Winqvist
- Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, University of Oulu, Biocenter Oulu
- Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institutet
- Argyrios Ziogas
- Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine
- kConFab/AOCS Investigators
- Peter MacCallum Cancer Center
- Kyriaki Michailidou
- Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge
- Georgia Chenevix-Trench
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute
- Thomas Bachelot
- Département de Cancérologie Médicale, Centre Léon Bérard
- Marjanka K. Schmidt
- Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital
- DOI
- https://doi.org/10.1038/s41598-021-99409-3
- Journal volume & issue
-
Vol. 11,
no. 1
pp. 1 – 11
Abstract
Abstract Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
