Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author(s): Shuai Li, MD, PhD1,2,3; Valentina Silvestri, PhD4; Goska Leslie, MEng2; Timothy R. Rebbeck, PhD5,6; Susan L. Neuhausen, PhD7; John L. Hopper, PhD1; Henriette Roed Nielsen, PhD8; Andrew Lee, CASM2; Xin Yang, PhD2; Lesley McGuffog2; Michael T. Parsons, BSc9; Irene L. Andrulis, PhD10,11; Norbert Arnold, PhD12,13; Muriel Belotti, PhD14,15; Åke Borg, PhD16; Bruno Buecher, MD14,15; Saundra S. Buys, MD17; Sandrine M. Caputo, PhD14,15; Wendy K. Chung, MD, PhD18; Chrystelle Colas, MD, PhD14,15; Sarah V. Colonna, MD17; Jackie Cook, MBBS19; Mary B. Daly, MD, PhD20; Miguel de la Hoya, PhD21; Antoine de Pauw, PhD14,15; Hélène Delhomelle, PhD14,15; Jacqueline Eason, MBChB, DM22; Christoph Engel, MD23; D. Gareth Evans, MD24,25; Ulrike Faust, PhD26; Tanja N. Fehm, MD27; Florentia Fostira, PhD28; George Fountzilas, MD, PhD29,30; Megan Frone, MSc31; Vanesa Garcia-Barberan, PhD21; Pilar Garre, PhD21; Marion Gauthier-Villars, MD14,15; Andrea Gehrig, PhD32; Gord Glendon, MSc10; David E. Goldgar, PhD33; Lisa Golmard, PharmD, PhD14,15; Mark H. Greene, MD31; Eric Hahnen, PhD34,35; Ute Hamann, PhD36; Helen Hanson, MBBS, MD37; Tiara Hassan, MGenCoun38; Julia Hentschel, PhD39; Judit Horvath, MD40; Louise Izatt, PhD41; Ramunas Janavicius, MD, PhD42,43; Yue Jiao, PhD44,45,46; Esther M. John, PhD47,48; Beth Y. Karlan, MD49; Sung-Won Kim, MD, PhD50; Irene Konstantopoulou, PhD28; Ava Kwong, MBBS, FRCS, PhD51,52,53; Anthony Laugé, MSc14,15; Jong Won Lee, PhD54; Fabienne Lesueur, PhD44,45,46; Noura Mebirouk, MSc44,45,46; Alfons Meindl, PhD55,56; Emmanuelle Mouret-Fourme, MD14,15; Hannah Musgrave, MSc57; Joanne Ngeow Yuen Yie, MBBS, MPH58,59; Dieter Niederacher, PhD27; Sue K. Park, MD, PhD60,61,62; Inge Sokilde Pedersen, PhD63,64,65; Juliane Ramser, PhD56; Susan J. Ramus, PhD66,67; Johanna Rantala, PhD68; Muhammad U. Rashid, MD, PhD36,69; Florian Reichl, MD70; Julia Ritter, PhD71; Andreas Rump, PhD72; Marta Santamariña, PhD73,74,75; Claire Saule, MD14,15; Gunnar Schmidt, PhD76; Rita K. Schmutzler, MD34,35,77; Leigha Senter, MSc78; Saba Shariff, MBBS79; Christian F. Singer, MD, MPH70; Melissa C. Southey, PhD3,80,81; Dominique Stoppa-Lyonnet, MD, PhD14,82,83; Christian Sutter, PhD84; Yen Tan, PhD70; Soo Hwang Teo, PhD38,85; Mary Beth Terry, PhD86; Mads Thomassen, PhD8; Marc Tischkowitz, MD, PhD87,88; Amanda E. Toland, PhD89; Diana Torres, PhD36,90; Ana Vega, PhD73,74,75; Sebastian A. Wagner, MD91; Shan Wang-Gohrke, MD, PhD92; Barbara Wappenschmidt, PhD34,35; Bernhard H. F. Weber, PhD93,94; Drakoulis Yannoukakos, PhD28; Amanda B. Spurdle, PhD9; Douglas F. Easton, PhD2; Georgia Chenevix-Trench, PhD9; Laura Ottini, MD4; and Antonis C. Antoniou, PhD2
Source: DOI: 10.1200/JCO.21.02112 Journal of Clinical Oncology 40, no. 14 (May 10, 2022) 1529-1541.
Lucio Gordan MD

Dr. Gordan's Thoughts

The importance of germline mutation assessment with the support of genetic counselors cannot be overestimated in daily practice. The impact can be very significant. Interesting to see the significantly elevated relative risk for GI cancers (pancreas, gastric) with BRCA 1 and 2 pathogenic variants.

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.

Author Affiliations

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

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