. 2022 May 10;40(14):1529-1541.

doi: 10.1200/JCO.21.02112. Epub 2022 Jan 25.

Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Shuai Li^{1

2

3}, Valentina Silvestri⁴, Goska Leslie², Timothy R Rebbeck^{5

6}, Susan L Neuhausen⁷, John L Hopper¹, Henriette Roed Nielsen⁸, Andrew Lee², Xin Yang², Lesley McGuffog², Michael T Parsons⁹, Irene L Andrulis^{10

11}, Norbert Arnold^{12

13}, Muriel Belotti^{14

15}, Åke Borg¹⁶, Bruno Buecher^{14

15}, Saundra S Buys¹⁷, Sandrine M Caputo^{14

15}, Wendy K Chung¹⁸, Chrystelle Colas^{14

15}, Sarah V Colonna¹⁷, Jackie Cook¹⁹, Mary B Daly²⁰, Miguel de la Hoya²¹, Antoine de Pauw^{14

15}, Hélène Delhomelle^{14

15}, Jacqueline Eason²², Christoph Engel²³, D Gareth Evans^{24

25}, Ulrike Faust²⁶, Tanja N Fehm²⁷, Florentia Fostira²⁸, George Fountzilas^{29

30}, Megan Frone³¹, Vanesa Garcia-Barberan²¹, Pilar Garre²¹, Marion Gauthier-Villars^{14

15}, Andrea Gehrig³², Gord Glendon¹⁰, David E Goldgar³³, Lisa Golmard^{14

15}, Mark H Greene³¹, Eric Hahnen^{34

35}, Ute Hamann³⁶, Helen Hanson³⁷, Tiara Hassan³⁸, Julia Hentschel³⁹, Judit Horvath⁴⁰, Louise Izatt⁴¹, Ramunas Janavicius^{42

43}, Yue Jiao^{44

45

46}, Esther M John^{47

48}, Beth Y Karlan⁴⁹, Sung-Won Kim⁵⁰, Irene Konstantopoulou²⁸, Ava Kwong^{51

52

53}, Anthony Laugé^{14

15}, Jong Won Lee⁵⁴, Fabienne Lesueur^{44

45

46}, Noura Mebirouk^{44

45

46}, Alfons Meindl^{55

56}, Emmanuelle Mouret-Fourme^{14

15}, Hannah Musgrave⁵⁷, Joanne Ngeow Yuen Yie^{58

59}, Dieter Niederacher²⁷, Sue K Park^{60

61

62}, Inge Sokilde Pedersen^{63

64

65}, Juliane Ramser⁵⁶, Susan J Ramus^{66

67}, Johanna Rantala⁶⁸, Muhammad U Rashid^{36

69}, Florian Reichl⁷⁰, Julia Ritter⁷¹, Andreas Rump⁷², Marta Santamariña^{73

74

75}, Claire Saule^{14

15}, Gunnar Schmidt⁷⁶, Rita K Schmutzler^{34

35

77}, Leigha Senter⁷⁸, Saba Shariff⁷⁹, Christian F Singer⁷⁰, Melissa C Southey^{3

80

81}, Dominique Stoppa-Lyonnet^{14

82

83}, Christian Sutter⁸⁴, Yen Tan⁷⁰, Soo Hwang Teo^{38

85}, Mary Beth Terry⁸⁶, Mads Thomassen⁸, Marc Tischkowitz^{87

88}, Amanda E Toland⁸⁹, Diana Torres^{36

90}, Ana Vega^{73

74

75}, Sebastian A Wagner⁹¹, Shan Wang-Gohrke⁹², Barbara Wappenschmidt^{34

35}, Bernhard H F Weber^{93

94}, Drakoulis Yannoukakos²⁸, Amanda B Spurdle⁹, Douglas F Easton², Georgia Chenevix-Trench⁹, Laura Ottini⁴, Antonis C Antoniou²

Affiliations

¹ Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
² Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
³ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁴ Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
⁵ Harvard T.H. Chan School of Public Health, Boston, MA.
⁶ Dana-Farber Cancer Institute, Boston, MA.
⁷ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA.
⁸ Department of Clinical Genetics, Odense University Hospital, Odence, Denmark.
⁹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹⁰ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
¹¹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹² Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹³ Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹⁴ Service de Génétique, Institut Curie, Paris, France.
¹⁵ Paris Sciences Lettres Research University, Paris, France.
¹⁶ Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
¹⁷ Department of Medicine and Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT.
¹⁸ Departments of Pediatrics and Medicine, Columbia University, New York, NY.
¹⁹ Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom.
²⁰ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA.
²¹ Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clinico San Carlos), Madrid, Spain.
²² Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
²³ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
²⁴ 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.
²⁵ North West Genomics Laboratory Hub, Manchester Center for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Center, Manchester, United Kingdom.
²⁶ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
²⁷ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
²⁸ Molecular Diagnostics Laboratory, INRASTES, National Center for Scientific Research "Demokritos", Athens, Greece.
²⁹ Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
³⁰ Department of Medical Oncology, German Oncology Center, Limassol, Cyprus.
³¹ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
³² Department of Human Genetics, University Würzburg, Würzburg, Germany.
³³ Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT.
³⁴ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³⁵ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³⁶ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁷ Southwest Thames Regional Genetics Service, St George's Hospital, London, United Kingdom.
³⁸ Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
³⁹ Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
⁴⁰ Institute of Human Genetics, University of Münster, Münster, Germany.
⁴¹ Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
⁴² Faculty of Medicine, Department of Human and Medical Genetics, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania.
⁴³ State Research Institute Center for Innovative Medicine, Vilnius, Lithuania.
⁴⁴ Genetic Epidemiology of Cancer Team, Inserm U900, Paris, France.
⁴⁵ Institut Curie, Paris, France.
⁴⁶ Mines ParisTech, Fontainebleau, France.
⁴⁷ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA.
⁴⁸ Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
⁴⁹ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
⁵⁰ Department of Surgery, Daerim Saint Mary's Hospital, Seoul, South Korea.
⁵¹ Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong.
⁵² Department of Surgery, The University of Hong Kong, Hong Kong.
⁵³ Department of Surgery and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong.
⁵⁴ Department of Surgery, Ulsan University College of Medicine and Asan Medical Center, Seoul, South Korea.
⁵⁵ Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
⁵⁶ Division of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
⁵⁷ Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
⁵⁸ Cancer Genetics Service, National Cancer Center, Singapore, Singapore.
⁵⁹ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
⁶⁰ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
⁶¹ Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea.
⁶² Cancer Research Institute, Seoul National University, Seoul, South Korea.
⁶³ Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.
⁶⁴ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
⁶⁵ Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
⁶⁶ Faculty of Medicine, School of Women's and Children's Health, University of NSW Sydney, Sydney, New South Wales, Australia.
⁶⁷ Adult Cancer Program, Lowy Cancer Research Center, University of NSW Sydney, Sydney, New South Wales, Australia.
⁶⁸ Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
⁶⁹ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Center (SKMCH & RC), Lahore, Pakistan.
⁷⁰ Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
⁷¹ Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁷² Faculty of Medicine Carl Gustav Carus, Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
⁷³ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
⁷⁴ Fundación Pública Galega Medicina Xenómica, Santiago De Compostela, Spain.
⁷⁵ Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago De Compostela, Spain.
⁷⁶ Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
⁷⁷ Faculty of Medicine, Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷⁸ Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH.
⁷⁹ West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, United Kingdom.
⁸⁰ Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
⁸¹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁸² Department of Tumour Biology, INSERM U830, Paris, France.
⁸³ Université Paris Descartes, Paris, France.
⁸⁴ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
⁸⁵ Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁸⁶ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY.
⁸⁷ Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
⁸⁸ Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
⁸⁹ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH.
⁹⁰ Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
⁹¹ Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, Frankfurt, Germany.
⁹² Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
⁹³ Institute of Human Genetics, University Regensburg, Regensburg, Germany.
⁹⁴ Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, Germany.

PMID: 35077220
PMCID: PMC9084432
DOI: 10.1200/JCO.21.02112

Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Shuai Li et al. J Clin Oncol. 2022.

. 2022 May 10;40(14):1529-1541.

doi: 10.1200/JCO.21.02112. Epub 2022 Jan 25.

Authors

Affiliations

¹ Center for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
² Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
³ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁴ Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
⁵ Harvard T.H. Chan School of Public Health, Boston, MA.
⁶ Dana-Farber Cancer Institute, Boston, MA.
⁷ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA.
⁸ Department of Clinical Genetics, Odense University Hospital, Odence, Denmark.
⁹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
¹⁰ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
¹¹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹² Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹³ Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹⁴ Service de Génétique, Institut Curie, Paris, France.
¹⁵ Paris Sciences Lettres Research University, Paris, France.
¹⁶ Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
¹⁷ Department of Medicine and Huntsman Cancer Institute, University of Utah Health, Salt Lake City, UT.
¹⁸ Departments of Pediatrics and Medicine, Columbia University, New York, NY.
¹⁹ Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom.
²⁰ Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA.
²¹ Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clinico San Carlos), Madrid, Spain.
²² Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.
²³ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
²⁴ 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.
²⁵ North West Genomics Laboratory Hub, Manchester Center for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Center, Manchester, United Kingdom.
²⁶ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
²⁷ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
²⁸ Molecular Diagnostics Laboratory, INRASTES, National Center for Scientific Research "Demokritos", Athens, Greece.
²⁹ Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
³⁰ Department of Medical Oncology, German Oncology Center, Limassol, Cyprus.
³¹ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
³² Department of Human Genetics, University Würzburg, Würzburg, Germany.
³³ Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT.
³⁴ Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³⁵ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³⁶ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
³⁷ Southwest Thames Regional Genetics Service, St George's Hospital, London, United Kingdom.
³⁸ Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
³⁹ Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
⁴⁰ Institute of Human Genetics, University of Münster, Münster, Germany.
⁴¹ Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
⁴² Faculty of Medicine, Department of Human and Medical Genetics, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania.
⁴³ State Research Institute Center for Innovative Medicine, Vilnius, Lithuania.
⁴⁴ Genetic Epidemiology of Cancer Team, Inserm U900, Paris, France.
⁴⁵ Institut Curie, Paris, France.
⁴⁶ Mines ParisTech, Fontainebleau, France.
⁴⁷ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA.
⁴⁸ Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
⁴⁹ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA.
⁵⁰ Department of Surgery, Daerim Saint Mary's Hospital, Seoul, South Korea.
⁵¹ Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong.
⁵² Department of Surgery, The University of Hong Kong, Hong Kong.
⁵³ Department of Surgery and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong.
⁵⁴ Department of Surgery, Ulsan University College of Medicine and Asan Medical Center, Seoul, South Korea.
⁵⁵ Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
⁵⁶ Division of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
⁵⁷ Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
⁵⁸ Cancer Genetics Service, National Cancer Center, Singapore, Singapore.
⁵⁹ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
⁶⁰ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
⁶¹ Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea.
⁶² Cancer Research Institute, Seoul National University, Seoul, South Korea.
⁶³ Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.
⁶⁴ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
⁶⁵ Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
⁶⁶ Faculty of Medicine, School of Women's and Children's Health, University of NSW Sydney, Sydney, New South Wales, Australia.
⁶⁷ Adult Cancer Program, Lowy Cancer Research Center, University of NSW Sydney, Sydney, New South Wales, Australia.
⁶⁸ Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
⁶⁹ Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Center (SKMCH & RC), Lahore, Pakistan.
⁷⁰ Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
⁷¹ Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
⁷² Faculty of Medicine Carl Gustav Carus, Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
⁷³ Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
⁷⁴ Fundación Pública Galega Medicina Xenómica, Santiago De Compostela, Spain.
⁷⁵ Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago De Compostela, Spain.
⁷⁶ Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
⁷⁷ Faculty of Medicine, Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷⁸ Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH.
⁷⁹ West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, United Kingdom.
⁸⁰ Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
⁸¹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁸² Department of Tumour Biology, INSERM U830, Paris, France.
⁸³ Université Paris Descartes, Paris, France.
⁸⁴ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
⁸⁵ Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
⁸⁶ Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY.
⁸⁷ Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
⁸⁸ Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.
⁸⁹ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH.
⁹⁰ Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia.
⁹¹ Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, Frankfurt, Germany.
⁹² Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
⁹³ Institute of Human Genetics, University Regensburg, Regensburg, Germany.
⁹⁴ Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, Germany.

PMID: 35077220
PMCID: PMC9084432
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.

PubMed Disclaimer

Conflict of interest statement

Timothy R. RebbeckHonoraria: AstraZeneca (I)Consulting or Advisory Role: AstraZeneca (I) Andrew LeeEmployment: IlluminaPatents, Royalties, Other Intellectual Property: I am an inventor of the BOADICEA model that is licensed to Cambridge Enterprise (part of the University of Cambridge) for commercialization. I have received royalties from Cambridge Enterprise. Norbert ArnoldHonoraria: AstraZeneca Åke BorgHonoraria: Roche, AstraZenecaTravel, Accommodations, Expenses: Roche, AstraZeneca Sandrine CaputoResearch Funding: AstraZeneca/France (Inst) Wendy K. ChungConsulting or Advisory Role: RegeneronResearch Funding: Biogen Chrystelle ColasConsulting or Advisory Role: AstraZeneca/Merck, Pfizer Miguel de la HoyaConsulting or Advisory Role: AstraZenecaResearch Funding: AstraZeneca D. Gareth EvansHonoraria: AstraZeneca Tanja N. FehmConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Daiichi Sankyo, MSD OncologyTravel, Accommodations, Expenses: Roche George FountzilasStock and Other Ownership Interests: GENPREX Inc (I), ARIAD (I), Deciphera Pharmaceuticals Inc (I), Daiichi Sankyo, RFL Holdings, FORMYCONHonoraria: AstraZenecaConsulting or Advisory Role: Pfizer, Roche, NovartisSpeakers' Bureau: Roche (I), LEO Pharma (I), Pfizer (I)Travel, Accommodations, Expenses: Merck (I), Pfizer (I), K.A.M Oncology/Hematology (I) Megan FronePatents, Royalties, Other Intellectual Property: Receive royalties for being a codeveloper of CancerGene Connect Eric HahnenConsulting or Advisory Role: AstraZeneca Helen HansonHonoraria: Pfizer Beth Y. KarlanConsulting or Advisory Role: Roche Pharma AG, Merck, Mercy Bioanalytics, GRAILResearch Funding: GOG Foundation (Inst), NCI-NRG Oncology (Inst), Genentech/Roche (Inst)Patents, Royalties, Other Intellectual Property: US and EU patent on gene signatureOther Relationship: Elsevier Irene KonstantopoulouSpeakers' Bureau: AstraZenecaResearch Funding: AstraZeneca Ava KwongHonoraria: Stryker, AstraZeneca Taiwan Limited, Roche Singapore, Pfizer, AstraZeneca Hong Kong Ltd Joanne Ngeow Yuen YieResearch Funding: AstraZeneca Rita K. SchmutzlerHonoraria: AstraZeneca, Clovis, MSD/AstraZenecaConsulting or Advisory Role: AstraZeneca, MSD/AstraZenecaResearch Funding: Amgen Leigha SenterConsulting or Advisory Role: AstraZeneca/MerckSpeakers' Bureau: AstraZeneca/Merck Christian F. SingerHonoraria: Novartis, AstraZeneca/MedImmune, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: AstraZeneca/MedImmune, Daiichi-Sankyo, Gilead Sciences, Sanofi/Aventis, NovartisSpeakers' Bureau: Novartis, AstraZeneca/MedImmuneResearch Funding: Novartis, Sanofi, Myriad Genetics, Roche, AstraZeneca/MedImmuneTravel, Accommodations, Expenses: Roche, Novartis Dominique Stoppa-LyonnetHonoraria: AstraZeneca/Merck (Inst) Soo Hwang TeoSpeakers' Bureau: AstraZeneca, Pfizer, Roche Sebastian A. WagnerConsulting or Advisory Role: Bayer Antonis C. AntoniouPatents, Royalties, Other Intellectual Property: Inventor of the BOADICEA model, which has been licensed to Cambridge Enterprise for commercialization. May receive royalties if commercialization is realized.No other potential conflicts of interest were reported.

Figures

**FIG 1.**
Age-specific absolute risks (%) and 95% CIs of primary cancers on the basis of UK cancer incidences in years 2008-2012 for (A) *BRCA1* and (B) *BRCA2* carriers. Solid lines are the age-specific absolute risk estimates, and ribbons are the relevant 95% CIs.

See this image and copyright information in PMC

Comment in

Do Female BRCA2 Pathogenic Variant Carriers Have an Increased Risk of Lung Cancer?
Fallet V, Sanchis-Borja M, Benusiglio PR, Cadranel J. Fallet V, et al. J Clin Oncol. 2022 Aug 1;40(22):2508. doi: 10.1200/JCO.22.00488. Epub 2022 May 12. J Clin Oncol. 2022. PMID: 35549390 No abstract available.

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Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Affiliations

Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

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