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dc.contributor.authorLee, Andrew
dc.contributor.authorYang, Xin
dc.contributor.authorTyrer, Jonathan
dc.contributor.authorGentry-Maharaj, Aleksandra
dc.contributor.authorRyan, Andy
dc.contributor.authorMavaddat, Nasim
dc.contributor.authorCunningham, Alex P
dc.contributor.authorCarver, Tim
dc.contributor.authorArcher, Stephanie
dc.contributor.authorLeslie, Goska
dc.contributor.authorKalsi, Jatinder
dc.contributor.authorGaba, Faiza
dc.contributor.authorManchanda, Ranjit
dc.contributor.authorGayther, Simon
dc.contributor.authorRamus, Susan J
dc.contributor.authorWalter, Fiona M
dc.contributor.authorTischkowitz, Marc
dc.contributor.authorJacobs, Ian
dc.contributor.authorMenon, Usha
dc.contributor.authorEaston, Douglas F
dc.contributor.authorPharoah, Paul
dc.contributor.authorAntoniou, Antonis C
dc.date.accessioned2022-01-10T12:51:57Z
dc.date.available2022-01-10T12:51:57Z
dc.date.issued2022-07
dc.date.submitted2021-04-07
dc.identifier.issn0022-2593
dc.identifier.otherjmedgenet-2021-107904
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332570
dc.descriptionFunder: Department of Health; FundRef: http://dx.doi.org/10.13039/501100000276
dc.descriptionFunder: Ontario Research Fund
dc.descriptionFunder: CHU de Quebec Foundation
dc.descriptionFunder: Fondation du cancer du sein du Québec; FundRef: http://dx.doi.org/10.13039/100016328
dc.descriptionFunder: The Eve Appeal
dc.description.abstractBACKGROUND: Epithelial tubo-ovarian cancer (EOC) has high mortality partly due to late diagnosis. Prevention is available but may be associated with adverse effects. A multifactorial risk model based on known genetic and epidemiological risk factors (RFs) for EOC can help identify women at higher risk who could benefit from targeted screening and prevention. METHODS: We developed a multifactorial EOC risk model for women of European ancestry incorporating the effects of pathogenic variants (PVs) in BRCA1, BRCA2, RAD51C, RAD51D and BRIP1, a Polygenic Risk Score (PRS) of arbitrary size, the effects of RFs and explicit family history (FH) using a synthetic model approach. The PRS, PV and RFs were assumed to act multiplicatively. RESULTS: Based on a currently available PRS for EOC that explains 5% of the EOC polygenic variance, the estimated lifetime risks under the multifactorial model in the general population vary from 0.5% to 4.6% for the first to 99th percentiles of the EOC risk distribution. The corresponding range for women with an affected first-degree relative is 1.9%-10.3%. Based on the combined risk distribution, 33% of RAD51D PV carriers are expected to have a lifetime EOC risk of less than 10%. RFs provided the widest distribution, followed by the PRS. In an independent partial model validation, absolute and relative 5-year risks were well calibrated in quintiles of predicted risk. CONCLUSION: This multifactorial risk model can facilitate stratification, in particular among women with FH of cancer and/or moderate-risk and high-risk PVs. The model is available via the CanRisk Tool (www.canrisk.org).
dc.languageen
dc.publisherBMJ
dc.subjectCancer genetics
dc.subject1506
dc.subjectgenetics
dc.subjectpublic health
dc.subjectearly diagnosis
dc.subjectclinical decision-making
dc.subjectgenetic counseling
dc.titleComprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors.
dc.typeArticle
dc.date.updated2022-01-10T12:51:56Z
prism.publicationNameJ Med Genet
dc.identifier.doi10.17863/CAM.80020
dcterms.dateAccepted2021-05-18
rioxxterms.versionofrecord10.1136/jmedgenet-2021-107904
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2021-11-21
dc.contributor.orcidLee, Andrew [0000-0003-0677-0252]
dc.contributor.orcidYang, Xin [0000-0003-0037-3790]
dc.contributor.orcidManchanda, Ranjit [0000-0003-3381-5057]
dc.contributor.orcidRamus, Susan J [0000-0003-0005-7798]
dc.contributor.orcidPharoah, Paul [0000-0001-8494-732X]
dc.contributor.orcidAntoniou, Antonis C [0000-0001-9223-3116]
dc.identifier.eissn1468-6244
pubs.funder-project-idCancer Research UK (20861)
cam.issuedOnline2021-11-29
rioxxterms.freetoread.startdate2021-11-21


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