Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

Taru A Muranen; Sofia Khan; Rainer Fagerholm; Kristiina Aittomäki; Julie M Cunningham; Joe Dennis; Goska Leslie; Lesley McGuffog; Michael T Parsons; Jacques Simard; Susan Slager; Penny Soucy; Douglas F Easton; Marc Tischkowitz; Amanda B Spurdle; kConFab Investigators; Rita K Schmutzler; Barbara Wappenschmidt; Eric Hahnen; Maartje J Hooning; HEBON Investigators; Christian F Singer; Gabriel Wagner; Mads Thomassen; Inge Sokilde Pedersen; Susan M Domchek; Katherine L Nathanson; Conxi Lazaro; Caroline Maria Rossing; Irene L Andrulis; Manuel R Teixeira; Paul James; Judy Garber; Jeffrey N Weitzel; SWE-BRCA Investigators; Anna Jakubowska; Drakoulis Yannoukakos; Esther M John; Melissa C Southey; Marjanka K Schmidt; Antonis C Antoniou; Georgia Chenevix-Trench; Carl Blomqvist; Heli Nevanlinna

doi:10.1038/s41523-020-00185-6

Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

NPJ Breast Cancer. 2020 Sep 10:6:44. doi: 10.1038/s41523-020-00185-6. eCollection 2020.

Authors

Taru A Muranen¹, Sofia Khan^{1

2}, Rainer Fagerholm¹, Kristiina Aittomäki³, Julie M Cunningham⁴, Joe Dennis⁵, Goska Leslie⁵, Lesley McGuffog⁵, Michael T Parsons⁶, Jacques Simard⁷, Susan Slager⁸, Penny Soucy⁷, Douglas F Easton^{5

9}, Marc Tischkowitz^{10

11}, Amanda B Spurdle⁶; kConFab Investigators; Rita K Schmutzler^{12

13}, Barbara Wappenschmidt^{12

13}, Eric Hahnen^{12

13}, Maartje J Hooning¹⁴; HEBON Investigators; Christian F Singer¹⁵, Gabriel Wagner¹⁵, Mads Thomassen¹⁶, Inge Sokilde Pedersen^{17

18}, Susan M Domchek¹⁹, Katherine L Nathanson¹⁹, Conxi Lazaro²⁰, Caroline Maria Rossing²¹, Irene L Andrulis^{22

23}, Manuel R Teixeira^{24

25}, Paul James^{26

27}, Judy Garber²⁸, Jeffrey N Weitzel²⁹; SWE-BRCA Investigators; Anna Jakubowska^{30

31}, Drakoulis Yannoukakos³², Esther M John³³, Melissa C Southey^{34

35}, Marjanka K Schmidt^{36

37}, Antonis C Antoniou⁵, Georgia Chenevix-Trench⁶, Carl Blomqvist^{38

39}, Heli Nevanlinna¹

Affiliations

¹ University of Helsinki, Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland.
² University of Turku and Åbo Akademi University, Turku Bioscience Centre, Turku, Finland.
³ University of Helsinki, Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland.
⁴ Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN USA.
⁵ University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK.
⁶ QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, QLD Australia.
⁷ CHU de Quebec Research Center, Genomics Center, Québec City, QC Canada.
⁸ Mayo Clinic, Department of Health Sciences Research, Rochester, MN USA.
⁹ University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK.
¹⁰ McGill University, Program in Cancer Genetics, Departments of Human Genetics and Oncology, Montréal, QC Canada.
¹¹ University of Cambridge, Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK.
¹² Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Hereditary Breast and Ovarian Cancer, Cologne, Germany.
¹³ Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
¹⁴ Erasmus MC Cancer Institute, Department of Medical Oncology, Family Cancer Clinic, Rotterdam, The Netherlands.
¹⁵ Medical University of Vienna, Dept of OB/GYN and Comprehensive Cancer Center, Vienna, Austria.
¹⁶ Odense University Hospital, Department of Clinical Genetics, Odence C, Denmark.
¹⁷ Aalborg University Hospital, Molecular Diagnostics, Aalborg, Denmark.
¹⁸ Aalborg University, Dept of Clinical Medicine, Aalborg, Denmark.
¹⁹ Perelman School of Medicine at the University of Pennsylvania, Department of Medicine, Abramson Cancer Center, Philadelphia, PA USA.
²⁰ ICO-IDIBELL (Bellvitge Biomedical Research Institute, Catalan Institute of Oncology), CIBERONC, Molecular Diagnostic Unit, Hereditary Cancer Program, Barcelona, Spain.
²¹ Rigshospitalet, Copenhagen University Hospital, Center for Genomic Medicine, Copenhagen, Denmark.
²² Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON Canada.
²³ University of Toronto, Department of Molecular Genetics, Toronto, ON Canada.
²⁴ Portuguese Oncology Institute, Department of Genetics, Porto, Portugal.
²⁵ University of Porto, Biomedical Sciences Institute (ICBAS), Porto, Portugal.
²⁶ Peter MacCallum Cancer Center, Parkville Familial Cancer Centre, Melbourne, VIC Australia.
²⁷ The University of Melbourne, Sir Peter MacCallum Department of Oncology, Melbourne, VIC Australia.
²⁸ Dana-Farber Cancer Institute, Cancer Risk and Prevention Clinic, Boston, MA USA.
²⁹ City of Hope, Clinical Cancer Genomics, Duarte, CA USA.
³⁰ Pomeranian Medical University, Department of Genetics and Pathology, Szczecin, Poland.
³¹ Pomeranian Medical University, Independent Laboratory of Molecular Biology and Genetic Diagnostics, Szczecin, Poland.
³² National Centre for Scientific Research 'Demokritos', Molecular Diagnostics Laboratory, INRASTES, Athens, Greece.
³³ Stanford Cancer Institute, Stanford University School of Medicine, Department of Medicine, Division of Oncology, Stanford, CA USA.
³⁴ Monash University, Precision Medicine, School of Clinical Sciences at Monash Health, Clayton, VIC Australia.
³⁵ The University of Melbourne, Department of Clinical Pathology, Melbourne, VIC Australia.
³⁶ The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Division of Molecular Pathology, Amsterdam, The Netherlands.
³⁷ The Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital, Division of Psychosocial Research and Epidemiology, Amsterdam, The Netherlands.
³⁸ University of Helsinki, Department of Oncology, Helsinki University Hospital, Helsinki, Finland.
³⁹ Örebro University Hospital, Department of Oncology, Örebro, Sweden.

Abstract

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 3.1 × 10^-9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

Keywords: Breast cancer; Cancer genetics; Genome-wide association studies.

Abstract

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