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Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.
Li, Hongyan; Engel, Christoph; de la Hoya, Miguel; Peterlongo, Paolo; Yannoukakos, Drakoulis; Livraghi, Luca; Radice, Paolo; Thomassen, Mads; Hansen, Thomas V O; Gerdes, Anne-Marie; Nielsen, Henriette R; Caputo, Sandrine M; Zambelli, Alberto; Borg, Ake; Solano, Angela; Thomas, Abigail; Parsons, Michael T; Antoniou, Antonis C; Leslie, Goska; Yang, Xin; Chenevix-Trench, Georgia; Caldes, Trinidad; Kwong, Ava; Pedersen, Inge Søkilde; Lautrup, Charlotte K; John, Esther M; Terry, Mary Beth; Hopper, John L; Southey, Melissa C; Andrulis, Irene L; Tischkowitz, Marc; Janavicius, Ramunas; Boonen, Susanne E; Kroeldrup, Lone; Varesco, Liliana; Hamann, Ute; Vega, Ana; Palmero, Edenir I; Garber, Judy; Montagna, Marco; Van Asperen, Christi J; Foretova, Lenka; Greene, Mark H; Selkirk, Tina; Moller, Pal; Toland, Amanda E; Domchek, Susan M; James, Paul A; Thorne, Heather; Eccles, Diana M.
Affiliation
  • Li H; Cancer Control and Population Science, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
  • Engel C; Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.
  • de la Hoya M; Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain.
  • Peterlongo P; Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, Milan, Italy.
  • Yannoukakos D; Molecular Diagnostics Laboratory, National Centre for Scientific Research "Demokritos", INRASTES Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, Athens, Greece.
  • Livraghi L; Medical Oncology Unit, AZIENDA SOCIO SANITARIA TERRITORIALE PAPA GIOVANNI XXIII, Bergamo, Italy; University of Siena, Siena, Italy.
  • Radice P; Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
  • Thomassen M; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  • Hansen TVO; Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Gerdes AM; Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
  • Nielsen HR; Department of Clinical Genetics Sygehus Lillebaelt, Vejle Hospital, Vejle, Denmark.
  • Caputo SM; Service de Génétique, Institut Curie, Paris, France; Paris Sciences and Lettres Research University, Paris, France.
  • Zambelli A; Medical Oncology Unit, AZIENDA SOCIO SANITARIA TERRITORIALE PAPA GIOVANNI XXIII, Bergamo, Italy.
  • Borg A; Divisions of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
  • Solano A; INBIOMED, Faculty of Medicine, University of Buenos Aires, CONICET and Genotyping Laboratory, Department of Clinical Chemistry, CEMIC, Buenos Aires, Argentina.
  • Thomas A; Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
  • Parsons MT; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  • Antoniou AC; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
  • Leslie G; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
  • Yang X; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
  • Chenevix-Trench G; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  • Caldes T; Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain.
  • Kwong A; Cancer Genetics Centre, Hong Kong Sanatorium & Hospital, Happy Valley, Hong Kong; Department of Surgery, LKS Faculty of Medicine,University of Hong Kong, Pok Fu Lam, Hong Kong.
  • Pedersen IS; Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark; Clinical Cancer Research Center and Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, The Faculty of Medicine, Aalborg University of Aalborg, Aalborg, Denmark.
  • Lautrup CK; Clinical Cancer Research Center and Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, The Faculty of Medicine, Aalborg University of Aalborg, Aalborg, Denmark.
  • John EM; Department of Epidemiology & Population Health and Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA.
  • Terry MB; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY.
  • Hopper JL; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
  • Southey MC; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia; Department of Clinical Pathology, Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Vi
  • Andrulis IL; Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • Tischkowitz M; Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, University of Cambridge, Cambridge, United Kingdom.
  • Janavicius R; Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania; State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
  • Boonen SE; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  • Kroeldrup L; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
  • Varesco L; Unit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
  • Hamann U; Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Vega A; Fundación Pública galega Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.
  • Palmero EI; Molecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil; National Cancer Institute, Rio de Janeiro, Brazil.
  • Garber J; Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA.
  • Montagna M; Immunology and Molecular Oncology Unit, IOV - Istituto Oncologico Veneto - IRCCS, Padova, Italy.
  • Van Asperen CJ; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
  • Foretova L; Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
  • Greene MH; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.
  • Selkirk T; NorthShore University HealthSystem, University of Chicago, Evanston, IL.
  • Moller P; Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Center for Hereditary Tumors, HELIOS-Klinikum Wuppertal, University of Witten-Herdecke, Wuppertal, Germany.
  • Toland AE; Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, OH.
  • Domchek SM; Basser Center for BRCA, Abramson Cancer Center, Penn Medicine, University of Pennsylvania, Philadelphia, PA.
  • James PA; Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; The Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
  • Thorne H; The Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Victoria, Australia.
  • Eccles DM; Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
Genet Med ; 24(1): 119-129, 2022 01.
Article in En | MEDLINE | ID: mdl-34906479
ABSTRACT

PURPOSE:

Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants.

METHODS:

We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis.

RESULTS:

Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P = .01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P = .005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs.

CONCLUSION:

These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ovarian Neoplasms / Breast Neoplasms Type of study: Etiology_studies / Prognostic_studies / Risk_factors_studies Limits: Female / Humans / Middle aged Language: En Journal: Genet Med Journal subject: GENETICA MEDICA Year: 2022 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ovarian Neoplasms / Breast Neoplasms Type of study: Etiology_studies / Prognostic_studies / Risk_factors_studies Limits: Female / Humans / Middle aged Language: En Journal: Genet Med Journal subject: GENETICA MEDICA Year: 2022 Document type: Article