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Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2

dc.contributor.authorO'Mahony, D.G.*
dc.contributor.authorRamus, S.J.*
dc.contributor.authorSouthey, M.C.*
dc.contributor.authorMeagher, N.S.*
dc.contributor.authorHadjisavvas, A.*
dc.contributor.authorJohn, E.M.*
dc.contributor.authorHamann, U.*
dc.contributor.authorImyanitov, E.N.*
dc.contributor.authorAndrulis, I.L.*
dc.contributor.authorSharma, P.*
dc.contributor.authorDaly, M.B.*
dc.contributor.authorHake, C.R.*
dc.contributor.authorWeitzel, J.N.*
dc.contributor.authorJakubowska, A.*
dc.contributor.authorGodwin, A.K.*
dc.contributor.authorArason, A.*
dc.contributor.authorBane, A.*
dc.contributor.authorSimard, J.*
dc.contributor.authorSoucy, P.*
dc.contributor.authorCaligo, M.A.*
dc.contributor.authorMai, P.L.*
dc.contributor.authorClaes, K.B.M.*
dc.contributor.authorTeixeira, M.R.*
dc.contributor.authorChung, W.K.*
dc.contributor.authorLazaro, C.*
dc.contributor.authorHulick, P.J.*
dc.contributor.authorToland, A.E.*
dc.contributor.authorPedersen, I.S.*
dc.contributor.authorMourits, M.J.E.*
dc.contributor.authorNeuhausen, S.L.*
dc.contributor.authorVega Gliemmo, Ana*
dc.contributor.authorde la Hoya, M.*
dc.contributor.authorNevanlinna, H.*
dc.contributor.authorDhawan, M.*
dc.contributor.authorZampiga, V.*
dc.contributor.authorDanesi, R.*
dc.contributor.authorVaresco, L.*
dc.contributor.authorGismondi, V.*
dc.contributor.authorVellone, V.G.*
dc.contributor.authorJames, P.A.*
dc.contributor.authorJanavicius, R.*
dc.contributor.authorNikitina-Zake, L.*
dc.contributor.authorNielsen, F.C.*
dc.contributor.authorvan Overeem Hansen, T.*
dc.contributor.authorPejovic, T.*
dc.contributor.authorBorg, A.*
dc.contributor.authorRantala, J.*
dc.contributor.authorOffit, K.*
dc.contributor.authorMontagna, M.*
dc.contributor.authorNathanson, K.L.*
dc.contributor.authorDomchek, S.M.*
dc.contributor.authorOsorio, A.*
dc.contributor.authorGarcía, M.J.*
dc.contributor.authorKarlan, B.Y.*
dc.contributor.authorLesueur, F.*
dc.contributor.authorDe Fazio, A.*
dc.contributor.authorBowtell, D.*
dc.contributor.authorDe Fazio, A.*
dc.contributor.authorMcGuffog, L.*
dc.contributor.authorLeslie, G.*
dc.contributor.authorParsons, M.T.*
dc.contributor.authorDörk, T.*
dc.contributor.authorSpeith, L.-M.*
dc.contributor.authordos Santos, E.S.*
dc.contributor.authorda Costa, A.A.B.A.*
dc.contributor.authorRadice, P.*
dc.contributor.authorPeterlongo, P.*
dc.contributor.authorPapi, L.*
dc.contributor.authorEngel, C.*
dc.contributor.authorHahnen, E.*
dc.contributor.authorSchmutzler, R.K.*
dc.contributor.authorWappenschmidt, B.*
dc.contributor.authorEaston, D.F.*
dc.contributor.authorTischkowitz, M.*
dc.contributor.authorSinger, C.F.*
dc.contributor.authorTan, Y.Y.*
dc.contributor.authorWhittemore, A.S.*
dc.contributor.authorSieh, W.*
dc.contributor.authorBrenton, J.D.*
dc.contributor.authorYannoukakos, D.*
dc.contributor.authorFostira, F.*
dc.contributor.authorKonstantopoulou, I.*
dc.contributor.authorSoukupova, J.*
dc.contributor.authorVocka, M.*
dc.contributor.authorChenevix-Trench, G.*
dc.contributor.authorPharoah, P.D.P.*
dc.contributor.authorAntoniou, A.C.*
dc.contributor.authorGoldgar, D.E.*
dc.contributor.authorSpurdle, A.B.*
dc.contributor.authorMichailidou, K.*
dc.contributor.authordos Santos, E.S.*
dc.date.accessioned2025-09-12T11:48:47Z
dc.date.available2025-09-12T11:48:47Z
dc.date.issued2023
dc.identifier.citationO'Mahony DG, Ramus SJ, Southey MC, Meagher NS, Hadjisavvas A, John EM, et al. Ovarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2. British Journal of Cancer. 2023;128(12):2283-94.
dc.identifier.issn1532-1827
dc.identifier.otherhttps://portalcientifico.sergas.gal//documentos/64609f8ec6d6be6c90fc6db6
dc.identifier.urihttp://hdl.handle.net/20.500.11940/21822
dc.description.abstractBackground: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) variant classification system. Methods: Data for 10,373 ovarian cancer cases, including carriers and non-carriers of BRCA1 or BRCA2 pathogenic variants, were collected from unpublished international cohorts and consortia and published studies. Likelihood ratios (LR) were calculated for the association of ovarian cancer histology and other characteristics, with BRCA1 and BRCA2 variant pathogenicity. Estimates were aligned to ACMG/AMP code strengths (supporting, moderate, strong). Results: No histological subtype provided informative ACMG/AMP evidence in favour of BRCA1 and BRCA2 variant pathogenicity. Evidence against variant pathogenicity was estimated for the mucinous and clear cell histologies (supporting) and borderline cases (moderate). Refined associations are provided according to tumour grade, invasion and age at diagnosis. Conclusions: We provide detailed estimates for predicting BRCA1 and BRCA2 variant pathogenicity based on ovarian tumour characteristics. This evidence can be combined with other variant information under the ACMG/AMP classification system, to improve classification and carrier clinical management.
dc.description.sponsorshipDenise G O'Mahony is supported by Telethon Cyprus (Telethon Cyprus: 33173233) through the Cyprus Institute of Neurology and Genetics. CIMBA: The CIMBA data management and data analysis were supported by Cancer Research-UK grants PPRPGM-Nov20100002 and C12292/A20861 and the Gray Foundation. ABS and SJR are supported by the NHMRC Investigator Fellowships (APP177524 and APP2009840). iCOGS: the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112-the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. OncoArray: the PERSPECTIVE and PERSPECTIVE I&I projects funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministere de l'Economie, de la Science et de l'Innovation du Quebec' through Genome Quebec, and the Quebec Breast Cancer Foundation; the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH Grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118 and C1287/A16563). AOCS was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania, The Cancer Foundation of Western Australia, and the National Health and Medical Research Council of Australia (NHMRC; ID199600, ID400413, ID400281). For the BCFR-NY, BCFR-PA this work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant P-MIP-22-187. BRICOH: SLN was partially supported by the Morris and Horowitz Families Endowed Professorship. CNIO: CNIO study is partially funded by Instituto de Salud Carlos III, project reference PI19/00640, cofunded by the European Regional Development Fund (ERDF), A way to make Europe and the Spanish Network on Rare Diseases (CIBERER). CCGCRN: Research reported in this publication was supported by the Breast Cancer Research Foundation (project 20-172), National Cancer Institute of the National Institutes of Health under grant number R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CONSIT TEAM: Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P. Peterlongo.CZECANCA: projects of the Ministry of Health of the Czech Republic (NU20-03-00016; RVO-VFN64165), Ministry of Education, Youth, and Sports of the Czech Republic (LX22NPO5102) and Charles University project COOPERATIO. DEMOKRITOS: European Union (European Social Fund-ESF) and Greek national funds through the Operational Program Education and Lifelong Learning of the National Strategic Reference Framework (NSRF) -Research funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants PRCPJT-Nov21100004, C1287/A23382 and C1287/A26886. D Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. The FCCC and KUMC cohorts: The University of Kansas Cancer Center (P30 CA168524), the Kansas Institute for Precision Medicine (P20GM130423) and the Kansas Bioscience Authority Eminent Scholar Program. AKG was funded by R01CA140323, R01CA214545, R01CA260132, 5U10CA180888, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX: A.Vega is supported by the Spanish Health Research Foundation, Instituto de Salud Carlos III (ISCIII), partially supported by FEDER funds through Research Activity Intensification Program (contract grant numbers: INT15/00070, INT16/00154, INT17/00133, INT20/00071), and through Centro de Investiga-cion Biomedica en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018); Autonomous Government of Galicia (Consolidation and structuring program: IN607B), and by the Fundacion Mutua Madrilena and Asociacion Espanola Contra el Cancer (AECC). GC-HBOC: German Cancer Aid (grant no 110837 and 113049, Rita K. Schmutzler), Federal Ministry of Education and Research, Germany (grant no 01GY1901), and the European Regional Development Fund and Free State of Saxony, Germany (LIFE -Leipzig Research Centre for Civilisation Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO, a study from the National Cancer Genetics Network UNICANCER Genetic Group, France.: Ligue Nationale Contre le Cancer; the Association Le cancer du sein, parlons-en! Award, the Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancerprogram, the Fondation ARC pour la recherche sur le cancer (grant PJA 20151203365) and the French National Institute of Cancer (INCa grants AOR 01 082, 2001-2003, 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). HCSC: Spanish Ministry of Science and Innovation, ISCIII (Hayley) cofunded by FEDER Regional Development European Funds (EU). HEBCS: Helsinki University Hospital Research Fund, the Finnish Cancer Society and the Sigrid Juselius Foundation.The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Netherlands Cancer Institute; Erasmus Medical Center, Rotterdam; Leiden University Medical Center; Radboud University Nijmegen Medical Center; University Medical Center Utrecht; Amsterdam UMC, Univ of Amsterdam; Amsterdam UMC, Vrije Universiteit Amsterdam; Maastricht University Medical Center; University of Gronin-gen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HJO: Ovarian cancer sequencing studies at Hannover Medical School were supported by the German Research Foundation (Do761/15-1). ICO: The authors would like to particularly acknowledge the support of the Asociacion Espanola Contra el Cancer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economia y Competitividad) and Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC) and the Institut Catala de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). IHCC: PBZ_KBN_122/P05/2004 and the program of the Minister of Science and Higher Education under the name Regional Initiative of Excellence in 2019-2022 project number 002/RID/2018/19 amount of financing12 000 000 PLN. INHERIT: Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program - grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade - grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and 5x1000 Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NNPIO: Russian Science Foundation (grant 21-75-30015). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University Comprehensive Cancer Center. SWE-BRCA: the Swedish Cancer Society. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Research UK. UPENN: Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA, NCI P30 CA016520. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. T.D. was funded by the German Research Foundation (Do761/ 15-1). MT (Marc Tischkowitz) was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014).
dc.languageeng
dc.rightsAttribution 4.0 International (CC BY 4.0)*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subject.meshHumans *
dc.subject.meshFemale *
dc.subject.meshVirulence *
dc.subject.meshBRCA1 Protein *
dc.subject.meshBRCA2 Protein *
dc.subject.meshOvarian Neoplasms *
dc.subject.meshGenetic Predisposition to Disease *
dc.subject.meshBreast Neoplasms *
dc.titleOvarian cancer pathology characteristics as predictors of variant pathogenicity in BRCA1 and BRCA2
dc.typeArtigo
dc.authorsophosO'Mahony, D.G.; Ramus, S.J.; Southey, M.C.; Meagher, N.S.; Hadjisavvas, A.; John, E.M.; Hamann, U.; Imyanitov, E.N.; Andrulis, I.L.; Sharma, P.; Daly, M.B.; Hake, C.R.; Weitzel, J.N.; Jakubowska, A.; Godwin, A.K.; Arason, A.; Bane, A.; Simard, J.; Soucy, P.; Caligo, M.A.; Mai, P.L.; Claes, K.B.M.; Teixeira, M.R.; Chung, W.K.; Lazaro, C.; Hulick, P.J.; Toland, A.E.; Pedersen, I.S.; Mourits, M.J.E.; Neuhausen, S.L.; Vega, A.; de la Hoya, M.; Nevanlinna, H.; Dhawan, M.; Zampiga, V.; Danesi, R.; Varesco, L.; Gismondi, V.; Vellone, V.G.; James, P.A.; Janavicius, R.; Nikitina-Zake, L.; Nielsen, F.C.; van Overeem Hansen, T.; Pejovic, T.; Borg, A.; Rantala, J.; Offit, K.; Montagna, M.; Nathanson, K.L.; Domchek, S.M.; Osorio, A.; García, M.J.; Karlan, B.Y.; Lesueur, F.; De Fazio, A.; Bowtell, D.; De Fazio, A.; McGuffog, L.; Leslie, G.; Parsons, M.T.; Dörk, T.; Speith, L.-M.; dos Santos, E.S.; da Costa, A.A.B.A.; Radice, P.; Peterlongo, P.; Papi, L.; Engel, C.; Hahnen, E.; Schmutzler, R.K.; Wappenschmidt, B.; Easton, D.F.; Tischkowitz, M.; Singer, C.F.; Tan, Y.Y.; Whittemore, A.S.; Sieh, W.; Brenton, J.D.; Yannoukakos, D.; Fostira, F.; Konstantopoulou, I.; Soukupova, J.; Vocka, M.; Chenevix-Trench, G.; Pharoah, P.D.P.; Antoniou, A.C.; Goldgar, D.E.; Spurdle, A.B.; Michailidou, K.; dos Santos, E.S.
dc.identifier.doi10.1038/s41416-023-02263-5
dc.identifier.sophos64609f8ec6d6be6c90fc6db6
dc.issue.number12
dc.journal.titleBritish Journal of Cancer*
dc.organizationFundación Pública Galega de Medicina Xenómica
dc.page.initial2283
dc.page.final2294
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dc.relation.projectIDBasser Research Center for BRCA
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dc.relation.projectIDCancer Research UK [22905] Funding Source: researchfish
dc.relation.projectIDAcademy of Finland (AKA) [110005] Funding Source: Academy of Finland (AKA)
dc.relation.publisherversionhttps://doi.org/10.1038/s41416-023-02263-5
dc.rights.accessRightsopenAccess*
dc.subject.keywordFPGMX
dc.typefidesArtículo Científico (incluye Original, Original breve, Revisión Sistemática y Meta-análisis)
dc.typesophosArtículo Original
dc.volume.number128


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O'Mahony DG, Ramus SJ, Southey MC, Meagher NS, Hadjisavvas A, John EM, et al. ...

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