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Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors

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 ri...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9252860/
https://www.ncbi.nlm.nih.gov/pubmed/34844974
http://dx.doi.org/10.1136/jmedgenet-2021-107904
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author 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
author_facet 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
author_sort Lee, Andrew
collection PubMed
description 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).
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spelling pubmed-92528602022-07-20 Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors 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 J Med Genet Cancer Genetics 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). BMJ Publishing Group 2022-07 2021-11-29 /pmc/articles/PMC9252860/ /pubmed/34844974 http://dx.doi.org/10.1136/jmedgenet-2021-107904 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
spellingShingle Cancer Genetics
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
Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors
title Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors
title_full Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors
title_fullStr Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors
title_full_unstemmed Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors
title_short Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors
title_sort comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors
topic Cancer Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9252860/
https://www.ncbi.nlm.nih.gov/pubmed/34844974
http://dx.doi.org/10.1136/jmedgenet-2021-107904
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