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Cited by 521BRCA gene mutations in cancerMultiple and Secondary Primary CancersGenetic factors in colorectal cancer

Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

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Rebbeck, Timothy R., Mitra, Nandita, Wan, Fei, Sinilnikova, Olga M., Healey, Sue, McGuffog, Lesley, Mazoyer, Sylvie, Chenevix-Trench, Georgia +250 more·2015·JAMA
DOI 10.1001/jama.2014.5985PMC PMC4537700
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Abstract

IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES: Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks. RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

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  • Carriers of pathogenic BRCA2 variants have a lifetime risk of developing breast cancer ranging from 38% to 84%.

    “Carriers of pathogenic BRCA2 variants have a lifetime risk of developing breast cancer ranging from 38% to 84%”

    From Screening, Risk Reduction Strategies, and Clinical Management of Unaffected Carriers of <i>BRCA1</i> or <i>BRCA2</i> Pathogenic Variants (2026) · cites this paper as [9]

    Methods > Statistical Analysis states an assumed lifetime breast cancer risk of 51% for BRCA2 carriers, and Results > Absolute Risks describes approximate mutation-specific risks by age 70. The passages do not substantiate the claimed 38%–84% range; the paper also cautions that its absolute-risk estimates are illustrative, not counseling estimates. Page numbers were not available in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Carriers of pathogenic BRCA2 variants have a lifetime risk of developing ovarian cancer ranging from 16.5% to 27.0%.

    “while the risk of developing ovarian cancer ranges from 16.5% to 27.0% [8, 9]”

    From Screening, Risk Reduction Strategies, and Clinical Management of Unaffected Carriers of <i>BRCA1</i> or <i>BRCA2</i> Pathogenic Variants (2026) · cites this paper as [9]

    The Methods (Statistical Analysis; page not provided) give an assumed BRCA2 ovarian cancer risk of 11% by age 70, and the Results (Absolute Risks; page not provided) explain that mutation-specific absolute risks are approximate. The copy supports variation in risk by BRCA2 mutation, but it does not substantiate the claimed 16.5%–27.0% lifetime range. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L., Mazoyer, S., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C., Nathanson, K. L., Laitman, Y., Kushnir, A., Paluch-Shimon, S., Berger, R., Zidan, J., Friedman, E., Ehrencrona, H., Stenmark-Askmalm, M., Einbeigi, Z., Loman, N., Harbst, K., Rantala, J., Melin, B., Huo, D., Olopade, O. I., Seldon, J., Ganz, P. A., Nussbaum, R. L., Chan, S. B., Odunsi, K., Gayther, S. A., Domchek, S. M., Arun, B. K., Lu, K. H., Mitchell, G., Karlan, B. Y., Walsh, C., Lester, J., Godwin, A. K., Pathak, H., Ross, E., Daly, M. B., Whittemore, A. S., John, E. M., Miron, A., Terry, M. B., Chung, W. K., Goldgar, D. E., Buys, S. S., Janavicius, R., Tihomirova, L., Tung, N., Dorfling, C. M., van Rensburg, E. J., Steele, L., Neuhausen, S. L., Ding, Y. C., Ejlertsen, B., Gerdes, A.-M., Hansen, T. V. O., Ramón y Cajal, T., Osorio, A., Benitez, J., Godino, J., Tejada, M.-I., Duran, M., Weitzel, J. N., Bobolis, K. A., Sand, S. R., Fontaine, A., Savarese, A., Pasini, B., Peissel, B., Bonanni, B., Zaffaroni, D., Vignolo-Lutati, F., Scuvera, G., Giannini, G., Bernard, L., Genuardi, M., Radice, P., Dolcetti, R., Manoukian, S., Pensotti, V., Gismondi, V., Yannoukakos, D., Fostira, F., Garber, J., Torres, D., Rashid, M. U., Hamann, U., Peock, S., Frost, D., Platte, R., Evans, D. G., Eeles, R., Davidson, R., Eccles, D., Cole, T., Cook, J., Brewer, C., Hodgson, S., Morrison, P. J., Walker, L., Porteous, M. E., Kennedy, M. J., Izatt, L., Adlard, J., Donaldson, A., Ellis, S., Sharma, P., Schmutzler, R. K., Wappenschmidt, B., Becker, A., Rhiem, K., Hahnen, E., Engel, C., Meindl, A., Engert, S., Ditsch, N., Arnold, N., Plendl, H. J., Mundhenke, C., Niederacher, D., Fleisch, M., Sutter, C., Bartram, C. R., Dikow, N., Wang-Gohrke, S., Gadzicki, D., Steinemann, D., Kast, K., Beer, M., Varon-Mateeva, R., Gehrig, A., Weber, B. H., Stoppa-Lyonnet, D., Sinilnikova, O. M., Mazoyer, S., Houdayer, C., Belotti, M., Gauthier-Villars, M., Damiola, F., Boutry-Kryza, N., Lasset, C., Sobol, H., Peyrat, J.-P., Muller, D., Fricker, J.-P., Collonge-Rame, M.-A., Mortemousque, I., Nogues, C., Rouleau, E., Isaacs, C., De Paepe, A., Poppe, B., Claes, K., De Leeneer, K., Piedmonte, M., Rodriguez, G., Wakely, K., Boggess, J., Blank, S. V., Basil, J., Azodi, M., Phillips, K.-A., Caldes, T., de la Hoya, M., Romero, A., Nevanlinna, H., Aittomäki, K., van der Hout, A. H., Hogervorst, F. B. L., Verhoef, S., Collée, J. M., Seynaeve, C., Oosterwijk, J. C., Gille, J. J. P., Wijnen, J. T., Garcia, E. B. G., Kets, C. M., Ausems, M. G. E. M., Aalfs, C. M., Devilee, P., Mensenkamp, A. R., Kwong, A., Olah, E., Papp, J., Diez, O., Lazaro, C., Darder, E., Blanco, I., Salinas, M., Jakubowska, A., Lubinski, J., Gronwald, J., Jaworska-Bieniek, K., Durda, K., Sukiennicki, G., Huzarski, T., Byrski, T., Cybulski, C., Toloczko-Grabarek, A., Zlowocka-Perlowska, E., Menkiszak, J., Arason, A., Barkardottir, R. B., Simard, J., Laframboise, R., Montagna, M., Agata, S., Alducci, E., Peixoto, A., Teixeira, M. R., Spurdle, A. B., Lee, M. H., Park, S. K., Kim, S.-W., Friebel, T. M., Couch, F. J., Lindor, N. M., Pankratz, V. S., Guidugli, L., Wang, X., Tischkowitz, M., Foretova, L., Vijai, J., Offit, K., Robson, M., Rau-Murthy, R., Kauff, N., Fink-Retter, A., Singer, C. F., Rappaport, C., Gschwantler-Kaulich, D., Pfeiler, G., Tea, M.-K., Berger, A., Greene, M. H., Mai, P. L., Imyanitov, E. N., Toland, A. E., Senter, L., Bojesen, A., Pedersen, I. S., Skytte, A.-B., Sunde, L., Thomassen, M., Moeller, S. T., Kruse, T. A., Jensen, U. B., Caligo, M. A., Aretini, P., Teo, S.-H., Selkirk, C. G., Hulick, P. J., & Andrulis, I.
Affiliations
  • Abramson Cancer Center (US)
  • University of Pennsylvania (US)
  • QIMR Berghofer Medical Research Institute (AU)
  • University of Cambridge (GB)
  • Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia
  • Sheba Medical Center (IL)
  • Sheba Medical Center, Tel Aviv, Israel
  • Rebecca Sieff Hospital (IL)
  • Uppsala University (SE)
  • Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  • Sahlgrenska University Hospital (SE)
  • Lund University (SE)
  • Karolinska University Hospital (SE)
  • Umeå University (SE)
  • University of Chicago Medical Center (US)
  • University of California, Los Angeles (US)
  • University of California, San Francisco (US)
  • Roswell Park Comprehensive Cancer Center (US)
  • University of Southern California (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • The University of Melbourne (AU)
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  • Beth Israel Deaconess Medical Center (US)
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  • Department of Genetics, University of Pretoria, Pretoria, South Africa
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  • Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
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  • Instituto Nazionale Tumori Regina Elena (IT)
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  • Institut Curie (FR)
  • Institut Curie, Department of Tumour Biology, Paris, France
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  • Service de Génétique Biologique-Histologie-Biologie du Développement et de la Reproduction, Centre Hospitalier Universitaire de Besançon, Besançon, France
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  • Center for Medical Genetics, Ghent University, Ghent, Belgium
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  • GOG Statistical and Data Center, Buffalo, New York
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  • Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain
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  • Department of Genetics, University Medical Center, Groningen University, Groningen, The Netherlands
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  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
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  • Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands
  • Radboud University Medical Center (NL)
  • University Medical Center Utrecht (NL)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Hong Kong Sanatorium and Hospital (HK)
  • Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
  • National Institute of Oncology (HU)
  • Oncogenetics Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, Barcelona, Spain139University Hospital of Vall d’Hebron, Barcelona, Spain
  • Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain
  • Institut Català d'Oncologia (ES)
  • Institut d'Investigació Biomédica de Bellvitge (ES)
  • Pomeranian Medical University (PL)
  • Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland144Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland
  • Department of Pathology, Landspitali University Hospital, Reykjavík, Iceland147BMC, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
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  • Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • National Institutes of Health (US)
  • Institute of Oncology NN Petrov (RU)
  • The Ohio State University (US)
  • Vejle Sygehus (DK)
  • Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
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  • Odense University Hospital (DK)
  • University of Pisa (IT)
  • University of Malaya (MY)
  • Endeavor Health (US)
  • Mount Sinai Hospital (CA)
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2015-04-07
Volume
313
Issue
13
Pages
1347
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2014.5985
PMC
PMC4537700
OpenAlex
W2029151927
Cited by
521
References
3
Citations by year
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FWCI
34.14
Type
journal article
Language
en
Open access
Licence
other-oa
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  • University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion, other-oa)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
  • Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
  • UpSpace Institutional Repository (University of Pretoria) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
  • Hirsla (Landspítali University Hospital) (submittedVersion)
  • Research Publications (Maastricht University) (submittedVersion)
Funders
  • U.S. Department of Defense
  • Breast Cancer Research Foundation
  • Amgen
  • AstraZeneca
  • University of Southern California
  • University of Pennsylvania
  • Beckman Research Institute, City of Hope
  • Deutsches Krebsforschungszentrum
  • Huntsman Cancer Institute
  • Cedars-Sinai Medical Center
  • Myriad Genetics
  • Cancer Research UK (11174, 15007, 16563, 17528)
  • National Institute for Health and Care Research (NF-SI-0510-10096)
  • National Breast Cancer Foundation
  • Cancer Association of South Africa
  • University of Pretoria
  • Trinity College Dublin
  • Institut National de la Santé et de la Recherche Médicale
  • Cancerfonden
  • Lunds Universitet
  • Linköpings Universitet
  • Peter MacCallum Cancer Centre
  • Centre National de la Recherche Scientifique
  • Umeå Universitet
  • Université Paris Descartes
  • Medizinischen Hochschule Hannover
  • Universität Regensburg
  • Sahlgrenska Universitetssjukhuset
  • Università degli Studi di Torino
  • Uppsala Universitet
  • Fondazione Italiana per la Ricerca sul Cancro
  • Universidad de Valladolid
  • Universität zu Köln
  • Julius-Maximilians-Universität Würzburg
  • Pontificia Universidad Javeriana
  • Universitätsklinikum Köln
  • National Institutes of Health (5r01ca112520-08, UL1TR001425, 1rc4ca153828-01)
  • School of Medicine, Stanford University
  • University of Texas MD Anderson Cancer Center
  • University of California, San Francisco
  • School of Medicine
  • National Cancer Institute (R01CA083855, R01CA140323, UG1CA189867, RC4-CA153828, UM1CA164920, U10CA037517, U10CA180868, U01CA113916, U01CA069398, R01CA102776, P50CA083638, U10CA027469, U10CA101165, U01CA069631, R01-CA112520, U01CA116167, P30CA012197, P30CA051008, P30CA016672, P50CA159981, U24CA196067, P30CA168524, P50CA116201, P30CA016520, R01CA074415, U10CA180822)
  • National Center for Advancing Translational Sciences
  • Jonsson Comprehensive Cancer Center
  • Janssen Pharmaceuticals
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Health Sciences › Medicine › Epidemiology › Multiple and Secondary Primary Cancers
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
BRCA1 mutation, BRCA2 mutation, breast cancer risk, ovarian cancer risk, germline mutations, cancer risk stratification, mutation carriers, hereditary cancer predisposition
MeSH terms
Adult, Breast Neoplasms, Female, Heterozygote, Humans, Middle Aged, Mutation, Nucleotides, Ovarian Neoplasms, Risk Factors, Age of Onset, Genes, BRCA1, Genetic Predisposition to Disease, Genes, BRCA2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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