PT  - JOURNAL ARTICLE
AU  - Lee, Andrew
AU  - Yang, Xin
AU  - Tyrer, Jonathan
AU  - Gentry-Maharaj, Aleksandra
AU  - Ryan, Andy
AU  - Mavaddat, Nasim
AU  - Cunningham, Alex P
AU  - Carver, Tim
AU  - Archer, Stephanie
AU  - Leslie, Goska
AU  - Kalsi, Jatinder
AU  - Gaba, Faiza
AU  - Manchanda, Ranjit
AU  - Gayther, Simon
AU  - Ramus, Susan J
AU  - Walter, Fiona M
AU  - Tischkowitz, Marc
AU  - Jacobs, Ian
AU  - Menon, Usha
AU  - Easton, Douglas F
AU  - Pharoah, Paul
AU  - Antoniou, Antonis C
TI  - Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors
AID  - 10.1136/jmedgenet-2021-107904
DP  - 2021 Nov 21
TA  - Journal of Medical Genetics
PG  - jmedgenet-2021-107904
4099  - http://jmg.bmj.com/content/early/2022/01/04/jmedgenet-2021-107904.short
4100  - http://jmg.bmj.com/content/early/2022/01/04/jmedgenet-2021-107904.full
AB  - 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).The model is freely available online (www.canrisk.org). For access to UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) dataset, which is subject to General Data Protection Regulations rules, please contact the UKCTOCS Biobank coordinator (s.apostolidou@ucl.ac.uk). The data access process is outlined online (http://uklwc.mrcctu.ucl.ac.uk/access-process/).