Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors. Issue 7 (29th November 2021)

• Record Type: Journal Article
• Authors: Lee, Andrew; Yang, Xin; Tyrer, Jonathan; Gentry-Maharaj, Aleksandra; Ryan, Andy; Mavaddat, Nasim; Cunningham, Alex P; Carver, Tim; Archer, Stephanie; Leslie, Goska; Kalsi, Jatinder; Gaba, Faiza; Manchanda, Ranjit; Gayther, Simon; Ramus, Susan J; Walter, Fiona M; Tischkowitz, Marc; Jacobs, Ian; Menon, Usha; Easton, Douglas F; Pharoah, Paul; Antoniou, Antonis C
• Is Part Of: Journal of medical genetics. Volume 59:Issue 7(2022)
• Page Start: 632
• Page End: 643
• Publication Date: 2021-11-29
• Subjects: genetics -- public health -- early diagnosis -- clinical decision-making -- genetic counseling; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2021-107904
• Languages: English
• ISSNs: 1468-6244

Abstract

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 ).