Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors.
J Med Genet
MetadataShow full item record
Lee, A., Yang, X., Tyrer, J., Gentry-Maharaj, A., Ryan, A., Mavaddat, N., Cunningham, A., et al. (2021). Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors.. J Med Genet https://doi.org/10.1136/jmedgenet-2021-107904
Funder: Department of Health; FundRef: http://dx.doi.org/10.13039/501100000276
Funder: Ontario Research Fund
Funder: CHU de Quebec Foundation
Funder: Fondation du cancer du sein du Québec; FundRef: http://dx.doi.org/10.13039/100016328
Funder: The Eve Appeal
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 (www.canrisk.org).
Cancer genetics, 1506, genetics, public health, early diagnosis, clinical decision-making, genetic counseling
Cancer Research UK (20861)
External DOI: https://doi.org/10.1136/jmedgenet-2021-107904
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332570