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Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

About this Publication
Title
Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.
Pubmed ID
34407845 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Breast Cancer Res. 2021 Aug 18; Volume 23 (Issue 1): Pages 86
Authors
Morra A, Escala-Garcia M, Beesley J, Keeman R, Canisius S, Ahearn TU, Andrulis IL, Anton-Culver H, Arndt V, Auer PL, Augustinsson A, Beane Freeman LE, Becher H, Beckmann MW, Behrens S, Bojesen SE, Bolla MK, Brenner H, Brüning T, Buys SS, ...show more Caan B, Campa D, Canzian F, Castelao JE, Chang-Claude J, Chanock SJ, Cheng TD, Clarke CL, NBCS Collaborators, Colonna SV, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Dennis J, Dörk T, Dossus L, Dunning AM, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Eriksson M, Evans DG, Fasching PA, Flyger H, Fritschi L, Gago-Dominguez M, García-Sáenz JA, Giles GG, Grip M, Guénel P, Gündert M, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Hart SN, Hartikainen JM, Hartmann A, He W, Hooning MJ, Hoppe R, Hopper JL, Howell A, Hunter DJ, ABCTB Investigators, kConFab Investigators, Jager A, Jakubowska A, Janni W, John EM, Jung AY, Kaaks R, Keupers M, Kitahara CM, Koutros S, Kraft P, Kristensen VN, Kurian AW, Lacey JV, Lambrechts D, Le Marchand L, Lindblom A, Linet M, Luben RN, Lubiński J, Lush M, Mannermaa A, Manoochehri M, Margolin S, Martens JWM, Martinez ME, Mavroudis D, Michailidou K, Milne RL, Mulligan AM, Muranen TA, Nevanlinna H, Newman WG, Nielsen SF, Nordestgaard BG, Olshan AF, Olsson H, Orr N, Park-Simon TW, Patel AV, Peissel B, Peterlongo P, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Presneau N, Rack B, Rennert G, Rennert HS, Rhenius V, Romero A, Roylance R, Ruebner M, Saloustros E, Sawyer EJ, Schmutzler RK, Schneeweiss A, Scott C, Shah M, Smichkoska S, Southey MC, Stone J, Surowy H, Swerdlow AJ, Tamimi RM, Tapper WJ, Teras LR, Terry MB, Tollenaar RAEM, Tomlinson I, Troester MA, Truong T, Vachon CM, Wang Q, Hurson AN, Winqvist R, Wolk A, Ziogas A, Brauch H, García-Closas M, Pharoah PDP, Easton DF, Chenevix-Trench G, Schmidt MK
Affiliations
  • Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
  • Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  • Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON, Canada.
  • Department of Medicine, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA, USA.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
  • Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany.
...show more
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Copenhagen University Hospital, Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark.
  • Department of Public Health and Primary Care, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK.
  • Institute of the Ruhr University Bochum (IPA), Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Bochum, Germany.
  • Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.
  • Division of Research, Kaiser Permanente, Oakland, CA, USA.
  • German Cancer Research Center (DKFZ), Genomic Epidemiology Group, Heidelberg, Germany.
  • Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Oncology and Genetics Unit, Vigo, Spain.
  • Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
  • Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Department of Oncology and Metabolism, University of Sheffield, Sheffield Institute for Nucleic Acids (SInFoNiA), Sheffield, UK.
  • Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
  • Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
  • Nutrition and Metabolism Section, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
  • Department of Oncology, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK.
  • School of Life Sciences, University of Westminster, London, UK.
  • Faculty of Medicine, University of Southampton, Southampton, UK.
  • Institute of Human Genetics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany.
  • Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Channing Division of Network Medicine, Boston, MA, USA.
  • Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
  • Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
  • School of Public Health, Curtin University, Perth, Western Australia, Australia.
  • Galician Public Foundation of Genomic Medicine (FPGMX), Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain.
  • Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
  • Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.
  • Team Exposome and Heredity, INSERM, University Paris-Saclay, Center for Research in Epidemiology and Population Health (CESP), Villejuif, France.
  • Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Faculty of Medicine and University Hospital Cologne, Center for Familial Breast and Ovarian Cancer, University of Cologne, Cologne, Germany.
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
  • Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
  • Institute of Pathology, Comprehensive Cancer Center Erlangen Nuremberg, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
  • Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
  • Division of Cancer Sciences, University of Manchester, Manchester, UK.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
  • Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
  • Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
  • Department of Radiation Oncology, University Hospitals Leuven, , University of Leuven, Leuven, Belgium.
  • Division of Cancer Epidemiology and Genetics, Radiation Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA.
  • Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • Department of Computational and Quantitative Medicine, City of Hope, Duarte, CA, USA.
  • VIB Center for Cancer Biology, Leuven, Belgium.
  • Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
  • Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
  • Clinical Gerontology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Department of Oncology, Södersjukhuset, Stockholm, Sweden.
  • University of California San Diego, Moores Cancer Center, La Jolla, CA, USA.
  • Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
  • Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
  • Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
  • Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
  • Department of Population Science, American Cancer Society, Atlanta, GA, USA.
  • Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
  • Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
  • MASA, Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Skopje, Republic of North Macedonia.
  • Carmel Medical Center and Technion Faculty of Medicine, Clalit National Cancer Control Center, Haifa, Israel.
  • Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
  • Department of Oncology, UCLH Foundation Trust, London, UK.
  • Department of Oncology, University Hospital of Larissa, Larissa, Greece.
  • School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
  • Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
  • Medical Faculty, University Clinic of Radiotherapy and Oncology, Ss. Cyril and Methodius University in Skopje, Skopje, Republic of North Macedonia.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
  • Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
  • Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
  • Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
  • Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
  • Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands. mk.schmidt@nki.nl.
Abstract

BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.

METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).

RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.

CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.

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