Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors.

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Tyrer, Jonathan 
Gentry-Maharaj, Aleksandra 
Ryan, Andy 

BACKGROUND: 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 (


Funder: Department of Health; FundRef:

Funder: Ontario Research Fund

Funder: CHU de Quebec Foundation

Funder: Fondation du cancer du sein du Québec; FundRef:

Funder: The Eve Appeal

clinical decision-making, early diagnosis, genetic counseling, genetics, public health, Breast Neoplasms, Carcinoma, Ovarian Epithelial, Female, Genetic Predisposition to Disease, Humans, Multifactorial Inheritance, Ovarian Neoplasms, Risk Factors
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J Med Genet
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Attribution 4.0 International
Cancer Research UK (20861)
European Research Council (310018)