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The impact of coding germline variants on contralateral breast cancer risk and survival.

About this Publication
Title
The impact of coding germline variants on contralateral breast cancer risk and survival.
Pubmed ID
36827971 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Am J Hum Genet. 2023 Mar 2; Volume 110 (Issue 3): Pages 475-486
Authors
Morra A, Mavaddat N, Muranen TA, Ahearn TU, Allen J, Andrulis IL, Auvinen P, Becher H, Behrens S, Blomqvist C, Bojesen SE, Bolla MK, Brauch H, Camp NJ, Carvalho S, Castelao JE, Cessna MH, Chang-Claude J, Chenevix-Trench G, NBCS Collaborators, ...show more Czene K, Decker B, Dennis J, Dörk T, Dorling L, Dunning AM, Ekici AB, Eriksson M, Evans DG, Fasching PA, Figueroa JD, Flyger H, Gago-Dominguez M, García-Closas M, Geurts-Giele WRR, Giles GG, Guénel P, Gündert M, Hahnen E, Hall P, Hamann U, Harrington PA, He W, Heikkilä P, Hooning MJ, Hoppe R, Howell A, Humphreys K, kConFab Investigators, Jakubowska A, Jung AY, Keeman R, Kristensen VN, Lubiński J, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Mavroudis D, Milne RL, Mulligan AM, Newman WG, Park-Simon TW, Peterlongo P, Pharoah PDP, Rhenius V, Saloustros E, Sawyer EJ, Schmutzler RK, Shah M, Spurdle AB, Tomlinson I, Truong T, van Veen EM, Vreeswijk MPG, Wang Q, Wendt C, Yang XR, Nevanlinna H, Devilee P, Easton DF, Schmidt MK
Affiliations
  • The Netherlands Cancer Institute, Division of Molecular Pathology, Plesmanlaan 121, 1066 Amsterdam, the Netherlands. Electronic address: a.morra@nki.nl.
  • University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK.
  • University of Helsinki, Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland.
  • National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA.
  • Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON, Canada; University of Toronto, Department of Molecular Genetics, Toronto, ON, Canada.
  • University of Eastern Finland, Translational Cancer Research Area, Kuopio, Finland; University of Eastern Finland, Institute of Clinical Medicine, Oncology, Kuopio, Finland; Kuopio University Hospital, Department of Oncology, Cancer Center, Kuopio, Finland.
  • University Medical Center Hamburg-Eppendorf, Institute of Medical Biometry and Epidemiology, Hamburg, Germany.
  • German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.
  • University of Helsinki, Department of Oncology, Helsinki University Hospital, Helsinki, Finland.
  • Copenhagen University Hospital, Copenhagen General Population Study, Herlev and Gentofte Hospital, Herlev, Denmark; Copenhagen University Hospital, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev, Denmark; University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
...show more
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, iFIT-Cluster of Excellence, Tübingen, Germany; German Cancer Consortium and German Cancer Research Center, Partner Site Tübingen, Tübingen, Germany.
  • University of Utah, Department of Internal Medicine and Huntsman Cancer Institute, Salt Lake City, UT, USA.
  • Instituto de Investigación Sanitaria Galicia Sur, Xerencia de Xestion Integrada de Vigo-SERGAS, Oncology and Genetics Unit, Vigo, Spain.
  • Intermountain Healthcare, Salt Lake City, UT, USA.
  • German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany; University Medical Center Hamburg-Eppendorf, Cancer Epidemiology Group, University Cancer Center Hamburg, Hamburg, Germany.
  • QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, QLD, Australia.
  • Oslo University Hospital-Radiumhospitalet, Department of Cancer Genetics, Institute for Cancer Research, Oslo, Norway; University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway; Vestre Viken Hospital, Department of Research, Drammen, Norway; Oslo University Hospital, Department of Tumor Biology, Institute for Cancer Research, Oslo, Norway; Oslo University Hospital-Radiumhospitalet, Department of Oncology, Division of Surgery, Cancer and Transplantation Medicine, Oslo, Norway; Akershus University Hospital, Department of Oncology, Lørenskog, Norway; Oslo University Hospital, Oslo Breast Cancer Research Consortium, Oslo, Norway; Oslo University Hospital and University of Oslo, Department of Medical Genetics, Oslo, Norway; The Arctic University of Norway, Department of Community Medicine, Tromsø, Norway; The Arctic University of Norway, Core Facility for Biobanking, Tromsø, Norway.
  • Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden.
  • University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK; Foundation Medicine, Inc, Pathology, Cambridge, MA, USA.
  • Hannover Medical School, Gynaecology Research Unit, Hannover, Germany.
  • University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK.
  • Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Institute of Human Genetics, Erlangen, Germany.
  • University of Manchester, Manchester Academic Health Science Centre, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester, UK; St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester, UK.
  • University Hospital Erlangen, Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
  • National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA; The University of Edinburgh, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK; The University of Edinburgh, Cancer Research UK Edinburgh Centre, Edinburgh, UK.
  • Copenhagen University Hospital, Department of Breast Surgery, Herlev and Gentofte Hospital, Herlev, Denmark.
  • Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario Universitario de Santiago, SERGAS, Genomic Medicine Group, International Cancer Genetics and Epidemiology Group, Santiago de Compostela, Spain; University of California San Diego, Moores Cancer Center, La Jolla, CA, USA.
  • Erasmus University Medical Center, Department of Clinical Genetics, Rotterdam, the Netherlands.
  • Cancer Council Victoria, Cancer Epidemiology Division, Melbourne, VIC, Australia; The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, VIC, Australia; Monash University, Precision Medicine, School of Clinical Sciences at Monash Health, Clayton, VIC, Australia.
  • INSERM, University Paris-Saclay, Center for Research in Epidemiology and Population Health, Team Exposome and Heredity, Villejuif, France.
  • German Cancer Research Center, Molecular Epidemiology Group, C080, Heidelberg, Germany; University of Heidelberg, Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, Heidelberg, Germany; Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Diabetes Research, Neuherberg, Germany.
  • Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Familial Breast and Ovarian Cancer, Cologne, Germany; Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Integrated Oncology, Cologne, Germany.
  • Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden; Södersjukhuset, Department of Oncology, Stockholm, Sweden.
  • German Cancer Research Center, Molecular Genetics of Breast Cancer, Heidelberg, Germany.
  • University of Helsinki, Department of Pathology, Helsinki University Hospital, Helsinki, Finland.
  • Erasmus MC Cancer Institute, Department of Medical Oncology, Rotterdam, the Netherlands.
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany.
  • University of Manchester, Division of Cancer Sciences, Manchester, UK.
  • Peter MacCallum Cancer Center, Research Department, Melbourne, VIC, Australia; The University of Melbourne, Sir Peter MacCallum Department of Oncology, Melbourne, VIC, Australia.
  • Pomeranian Medical University, Department of Genetics and Pathology, International Hereditary Cancer Center, Szczecin, Poland; Pomeranian Medical University, Independent Laboratory of Molecular Biology and Genetic Diagnostics, Szczecin, Poland.
  • The Netherlands Cancer Institute, Division of Molecular Pathology, Plesmanlaan 121, 1066 Amsterdam, the Netherlands.
  • University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway; Oslo University Hospital and University of Oslo, Department of Medical Genetics, Oslo, Norway.
  • Pomeranian Medical University, Department of Genetics and Pathology, International Hereditary Cancer Center, Szczecin, Poland.
  • University of Eastern Finland, Translational Cancer Research Area, Kuopio, Finland; University of Eastern Finland, Institute of Clinical Medicine, Pathology and Forensic Medicine, Kuopio, Finland; Kuopio University Hospital, Biobank of Eastern Finland, Kuopio, Finland.
  • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Unit of Medical Genetics, Department of Medical Oncology and Hematology, Milan, Italy.
  • Södersjukhuset, Department of Oncology, Stockholm, Sweden; Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Stockholm, Sweden.
  • University Hospital of Heraklion, Department of Medical Oncology, Heraklion, Greece.
  • University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, ON, Canada; University Health Network, Laboratory Medicine Program, Toronto, ON, Canada.
  • IFOM ETS - the AIRC Institute of Molecular Oncology, Genome Diagnostics Program, Milan, Italy.
  • University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Cambridge, UK; University of Cambridge, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK.
  • University Hospital of Larissa, Department of Oncology, Larissa, Greece.
  • King's College London, School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, London, UK.
  • Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Familial Breast and Ovarian Cancer, Cologne, Germany; Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Integrated Oncology, Cologne, Germany; Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.
  • QIMR Berghofer Medical Research Institute, Population Health Program, Brisbane, QLD, Australia.
  • University of Birmingham, Institute of Cancer and Genomic Sciences, Birmingham, UK; University of Oxford, Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, Oxford, UK.
  • Leiden University Medical Center, Department of Human Genetics, Leiden, the Netherlands.
  • Leiden University Medical Center, Department of Human Genetics, Leiden, the Netherlands; Leiden University Medical Center, Department of Pathology, Leiden, the Netherlands.
  • The Netherlands Cancer Institute, Division of Molecular Pathology, Plesmanlaan 121, 1066 Amsterdam, the Netherlands; The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Division of Psychosocial Research and Epidemiology, Amsterdam, the Netherlands. Electronic address: mk.schmidt@nki.nl.
Abstract

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.

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