Shuai Li1,2,3, Valentina Silvestri4, Goska Leslie2, Timothy R Rebbeck5,6, Susan L Neuhausen7, John L Hopper1, Henriette Roed Nielsen8, Andrew Lee2, Xin Yang2, Lesley McGuffog2, Michael T Parsons9, Irene L Andrulis10,11, Norbert Arnold12,13, Muriel Belotti14,15, Åke Borg16, Bruno Buecher14,15, Saundra S Buys17, Sandrine M Caputo14,15, Wendy K Chung18, Chrystelle Colas14,15, Sarah V Colonna17, Jackie Cook19, Mary B Daly20, Miguel de la Hoya21, Antoine de Pauw14,15, Hélène Delhomelle14,15, Jacqueline Eason22, Christoph Engel23, D Gareth Evans24,25, Ulrike Faust26, Tanja N Fehm27, Florentia Fostira28, George Fountzilas29,30, Megan Frone31, Vanesa Garcia-Barberan21, Pilar Garre21, Marion Gauthier-Villars14,15, Andrea Gehrig32, Gord Glendon10, David E Goldgar33, Lisa Golmard14,15, Mark H Greene31, Eric Hahnen34,35, Ute Hamann36, Helen Hanson37, Tiara Hassan38, Julia Hentschel39, Judit Horvath40, Louise Izatt41, Ramunas Janavicius42,43, Yue Jiao44,45,46, Esther M John47,48, Beth Y Karlan49, Sung-Won Kim50, Irene Konstantopoulou28, Ava Kwong51,52,53, Anthony Laugé14,15, Jong Won Lee54, Fabienne Lesueur44,45,46, Noura Mebirouk44,45,46, Alfons Meindl55,56, Emmanuelle Mouret-Fourme14,15, Hannah Musgrave57, Joanne Ngeow Yuen Yie58,59, Dieter Niederacher27, Sue K Park60,61,62, Inge Sokilde Pedersen63,64,65, Juliane Ramser56, Susan J Ramus66,67, Johanna Rantala68, Muhammad U Rashid36,69, Florian Reichl70, Julia Ritter71, Andreas Rump72, Marta Santamariña73,74,75, Claire Saule14,15, Gunnar Schmidt76, Rita K Schmutzler34,35,77, Leigha Senter78, Saba Shariff79, Christian F Singer70, Melissa C Southey3,80,81, Dominique Stoppa-Lyonnet14,82,83, Christian Sutter84, Yen Tan70, Soo Hwang Teo38,85, Mary Beth Terry86, Mads Thomassen8, Marc Tischkowitz87,88, Amanda E Toland89, Diana Torres36,90, Ana Vega73,74,75, Sebastian A Wagner91, Shan Wang-Gohrke92, Barbara Wappenschmidt34,35, Bernhard H F Weber93,94, Drakoulis Yannoukakos28, Amanda B Spurdle9, Douglas F Easton2, Georgia Chenevix-Trench9, Laura Ottini4, Antonis C Antoniou2. 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.
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.
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.
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