Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors.
Authors
Tyrer, Jonathan
Gentry-Maharaj, Aleksandra
Ryan, Andy
Mavaddat, Nasim
Cunningham, Alex P
Carver, Tim
Archer, Stephanie
Leslie, Goska
Kalsi, Jatinder
Gaba, Faiza
Gayther, Simon
Walter, Fiona M
Tischkowitz, Marc
Jacobs, Ian
Menon, Usha
Easton, Douglas F
Publication Date
2022-07Journal Title
J Med Genet
ISSN
0022-2593
Publisher
BMJ
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Lee, A., Yang, X., Tyrer, J., Gentry-Maharaj, A., Ryan, A., Mavaddat, N., Cunningham, A. P., et al. (2022). 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
Description
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
Abstract
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).
Keywords
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
Sponsorship
Cancer Research UK (20861)
European Research Council (310018)
Identifiers
jmedgenet-2021-107904
External DOI: https://doi.org/10.1136/jmedgenet-2021-107904
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332570
Rights
Licence:
https://creativecommons.org/licenses/by/4.0/
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