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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
H. Li, C. Engel, M. de la Hoya, P. Peterlongo, D. Yannoukakos, L. Livraghi, P. Radice, M. Thomassen, TVO. Hansen, AM. Gerdes, HR. Nielsen, SM. Caputo, A. Zambelli, A. Borg, A. Solano, A. Thomas, MT. Parsons, AC. Antoniou, G. Leslie, X. Yang, G....
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
R35 CA253187
NCI NIH HHS - United States
R01 CA225662
NCI NIH HHS - United States
R01 CA116167
NCI NIH HHS - United States
P50 CA116201
NCI NIH HHS - United States
C12292/A20861
Cancer Research UK - United Kingdom
UM1 CA164920
NCI NIH HHS - United States
- MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Testing methods MeSH
- Genes, BRCA1 MeSH
- Genes, BRCA2 MeSH
- Middle Aged MeSH
- Humans MeSH
- Breast Neoplasms * genetics pathology MeSH
- Ovarian Neoplasms * genetics MeSH
- BRCA1 Protein genetics MeSH
- BRCA2 Protein genetics MeSH
- Germ-Line Mutation genetics MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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.
Cancer Control and Population Science Huntsman Cancer Institute University of Utah Salt Lake City UT
Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia
Cancer Genetics Centre Hong Kong Sanatorium and Hospital Happy Valley Hong Kong
Center for Cancer Genetics and Prevention Dana Farber Cancer Institute Boston MA
Center for Clinical Cancer Genetics The University of Chicago Chicago IL
Center for Integrated Oncology Faculty of Medicine University of Cologne Cologne Germany
Department of Cancer Biology and Genetics College of Medicine The Ohio State University Columbus OH
Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic
Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands
Department of Clinical Genetics Odense University Hospital Odense Denmark
Department of Clinical Genetics Rigshospitalet Copenhagen University Hospital Copenhagen Denmark
Department of Clinical Genetics Sygehus Lillebaelt Vejle Hospital Vejle Denmark
Department of Dermatology University of Utah School of Medicine Salt Lake City UT
Department of Epidemiology Mailman School of Public Health Columbia University New York NY
Department of Health Sciences Research Mayo Clinic Rochester MN
Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN
Department of Molecular Genetics University of Toronto Toronto Ontario Canada
Department of Surgery LKS Faculty of Medicine University of Hong Kong Pok Fu Lam Hong Kong
Divisions of Oncology and Pathology Department of Clinical Sciences Lund Lund University Lund Sweden
Faculty of Medicine University of Southampton Southampton United Kingdom
Genome Diagnostics Program IFOM the FIRC Institute of Molecular Oncology Milan Italy
Herbert Irving Comprehensive Cancer Center Columbia University New York NY
Immunology and Molecular Oncology Unit IOV Istituto Oncologico Veneto IRCCS Padova Italy
Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany
Medical Genetics Unit Department of Medical Sciences University of Torino Torino Italy
Medical Oncology Unit AZIENDA SOCIO SANITARIA TERRITORIALE PAPA GIOVANNI XXIII Bergamo Italy
Molecular Diagnostics Aalborg University Hospital Aalborg Denmark
Molecular Genetics of Breast Cancer German Cancer Research Center Heidelberg Germany
Molecular Oncology Research Center Barretos Cancer Hospital São Paulo Brazil
National Cancer Institute Rio de Janeiro Brazil
NorthShore University HealthSystem University of Chicago Evanston IL
Paris Sciences and Lettres Research University Paris France
Parkville Familial Cancer Centre Peter MacCallum Cancer Centre Melbourne Victoria Australia
Service de Génétique Institut Curie Paris France
SOD Genetica Molecolare University Hospital Pisa Italy
State Research Institute Centre for Innovative Medicine Vilnius Lithuania
Unit of Hereditary Cancer IRCCS Ospedale Policlinico San Martino Genoa Italy
References provided by Crossref.org
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- $a Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants / $c H. Li, C. Engel, M. de la Hoya, P. Peterlongo, D. Yannoukakos, L. Livraghi, P. Radice, M. Thomassen, TVO. Hansen, AM. Gerdes, HR. Nielsen, SM. Caputo, A. Zambelli, A. Borg, A. Solano, A. Thomas, MT. Parsons, AC. Antoniou, G. Leslie, X. Yang, G. Chenevix-Trench, T. Caldes, A. Kwong, IS. Pedersen, CK. Lautrup, EM. John, MB. Terry, JL. Hopper, MC. Southey, IL. Andrulis, M. Tischkowitz, R. Janavicius, SE. Boonen, L. Kroeldrup, L. Varesco, U. Hamann, A. Vega, EI. Palmero, J. Garber, M. Montagna, CJ. Van Asperen, L. Foretova, MH. Greene, T. Selkirk, P. Moller, AE. Toland, SM. Domchek, PA. James, H. Thorne, DM. Eccles, SM. Nielsen, S. Manoukian, B. Pasini, MA. Caligo, C. Lazaro, J. Kirk, B. Wappenschmidt, AB. Spurdle, FJ. Couch, R. Schmutzler, DE. Goldgar, ENIGMA Consortium, CIMBA Consortium
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- $a 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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