| Autor: |
Douglas F. Easton, Nasim Mavaddat, Andy Ryan, Jonathan Tyrer, Goska Leslie, Usha Menon, Alex P Cunningham, Simon A. Gayther, Ian Jacobs, Paul P.D. Pharoah, Aleksandra Gentry-Maharaj, Marc Tischkowitz, Andrew Lee, Ranjit Manchanda, Antonis C. Antoniou, Stephanie Archer, Susan J. Ramus, Tim Carver, Xin Yang, Fiona M Walter, Jatinderpal Kalsi, Faiza Gaba |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.12.04.20244046 |
| Popis: |
BackgroundEpithelial 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 females at higher risk who could benefit from targeted screening and prevention.MethodsWe developed a multifactorial EOC risk model for females of European ancestry incorporating the effects of pathogenic variants (PVs) inBRCA1, BRCA2, RAD51C, RAD51DandBRIP1, 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.ResultsBased 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 1stto 99thpercentiles of the EOC risk-distribution. The corresponding range for females with an affected first-degree relative is 1.9% to 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.ConclusionThis multifactorial risk model can facilitate stratification, in particular among females with FH of cancer and/or moderate- and high-risk PVs. The model is available via the CanRisk Tool (www.canrisk.org). |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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