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Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Li S 1 , Silvestri V 2 , Leslie G 3 , Rebbeck TR 4 , Neuhausen SL 5 , Hopper JL 1 Show all authors , Nielsen HR 6 , Lee A 3 , Yang X 3 , McGuffog L 3 , Parsons MT 7 , Andrulis IL 8 , Arnold N 9 , Belotti M 10 , Borg Å 11 , Buecher B 10 , Buys SS 12 , Caputo SM 10 , Chung WK 13 , Colas C 10 , Colonna SV 12 , Cook J 14 , Daly MB 15 , de la Hoya M 16 , de Pauw A 10 , Delhomelle H 10 , Eason J 17 , Engel C 18 , Evans DG 19 , Faust U 20 , Fehm TN 21 , Fostira F 22 , Fountzilas G 23 , Frone M 24 , Garcia-Barberan V 16 , Garre P 16 , Gauthier-Villars M 10 , Gehrig A 25 , Glendon G 8 , Goldgar DE 26 , Golmard L 10 , Greene MH 24 , Hahnen E 27 , Hamann U 28 , Hanson H 29 , Hassan T 30 , Hentschel J 31 , Horvath J 32 , Izatt L 33 , Janavicius R 34 , Jiao Y 35 , John EM 36 , Karlan BY 37 , Kim SW 38 , Konstantopoulou I 22 , Kwong A 39 , Laugé A 10 , Lee JW 40 , Lesueur F 35 , Mebirouk N 35 , Meindl A 41 , Mouret-Fourme E 10 , Musgrave H 42 , Ngeow Yuen Yie J 43 , Niederacher D 21 , Park SK 44 , Pedersen IS 45 , Ramser J 46 , Ramus SJ 47 , Rantala J 48 , Rashid MU 28 , Reichl F 49 , Ritter J 50 , Rump A 51 , Santamariña M 52 , Saule C 10 , Schmidt G 53 , Schmutzler RK 27 , Senter L 54 , Shariff S 55 , Singer CF 49 , Southey MC 56 , Stoppa-Lyonnet D 10 , Sutter C 57 , Tan Y 49 , Teo SH 30 , Terry MB 58 , Thomassen M 6 , Tischkowitz M 59 , Toland AE 60 , Torres D 28 , Vega A 52 , Wagner SA 61 , Wang-Gohrke S 62 , Wappenschmidt B 27 , Weber BHF 63 , Yannoukakos D 22 , Spurdle AB 7 , Easton DF 3 , Chenevix-Trench G 7 , Ottini L 2 , Antoniou AC 3

Affiliations 

  • 1 Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
  • 2 Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
  • 3 Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
  • 4 Harvard T.H. Chan School of Public Health, Boston, MA
  • 5 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA
  • 6 Department of Clinical Genetics, Odense University Hospital, Odence, Denmark
  • 7 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 8 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
  • 9 Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany
  • 10 Service de Génétique, Institut Curie, Paris, France
  • 11 Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
  • 12 Department of Medicine and Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT
  • 13 Departments of Pediatrics and Medicine, Columbia University, New York, NY
  • 14 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom
  • 15 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA
  • 16 Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clinico San Carlos), Madrid, Spain
  • 17 Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
  • 18 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  • 19 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Center, Manchester, United Kingdom
  • 20 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
  • 21 Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
  • 22 Molecular Diagnostics Laboratory, INRASTES, National Center for Scientific Research "Demokritos", Athens, Greece
  • 23 Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
  • 24 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
  • 25 Department of Human Genetics, University Würzburg, Würzburg, Germany
  • 26 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT
  • 27 Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • 28 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 29 Southwest Thames Regional Genetics Service, St George's Hospital, London, United Kingdom
  • 30 Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  • 31 Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany
  • 32 Institute of Human Genetics, University of Münster, Münster, Germany
  • 33 Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
  • 34 Faculty of Medicine, Department of Human and Medical Genetics, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania
  • 35 Genetic Epidemiology of Cancer Team, Inserm U900, Paris, France
  • 36 Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA
  • 37 Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA
  • 38 Department of Surgery, Daerim Saint Mary's Hospital, Seoul, South Korea
  • 39 Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong
  • 40 Department of Surgery, Ulsan University College of Medicine and Asan Medical Center, Seoul, South Korea
  • 41 Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany
  • 42 Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
  • 43 Cancer Genetics Service, National Cancer Center, Singapore, Singapore
  • 44 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea
  • 45 Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark
  • 46 Division of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
  • 47 Faculty of Medicine, School of Women's and Children's Health, University of NSW Sydney, Sydney, New South Wales, Australia
  • 48 Clinical Genetics, Karolinska Institutet, Stockholm, Sweden
  • 49 Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • 50 Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • 51 Faculty of Medicine Carl Gustav Carus, Institute for Clinical Genetics, TU Dresden, Dresden, Germany
  • 52 Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain
  • 53 Institute of Human Genetics, Hannover Medical School, Hannover, Germany
  • 54 Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH
  • 55 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, United Kingdom
  • 56 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
  • 57 Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
  • 58 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
  • 59 Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada
  • 60 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH
  • 61 Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, Frankfurt, Germany
  • 62 Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
  • 63 Institute of Human Genetics, University Regensburg, Regensburg, Germany
J Clin Oncol, 2022 May 10;40(14):1529-1541.
PMID: 35077220 DOI: 10.1200/JCO.21.02112

Abstract

PURPOSE: To provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.

METHODS: We used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.

RESULTS: BRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.

CONCLUSION: In addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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