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Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2

SIMPLE SUMMARY: Germline and somatic variant testing of the BRCA1 and BRCA2 genes are important to predict treatment response to PARP inhibitors in ovarian cancer patients. However, germline variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which woul...

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Autores principales: Barbosa, Ana, Pinto, Pedro, Peixoto, Ana, Guerra, Joana, Pinto, Carla, Santos, Catarina, Pinheiro, Manuela, Escudeiro, Carla, Bartosch, Carla, Silva, João, Teixeira, Manuel R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650720/
https://www.ncbi.nlm.nih.gov/pubmed/33008098
http://dx.doi.org/10.3390/cancers12102834
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author Barbosa, Ana
Pinto, Pedro
Peixoto, Ana
Guerra, Joana
Pinto, Carla
Santos, Catarina
Pinheiro, Manuela
Escudeiro, Carla
Bartosch, Carla
Silva, João
Teixeira, Manuel R.
author_facet Barbosa, Ana
Pinto, Pedro
Peixoto, Ana
Guerra, Joana
Pinto, Carla
Santos, Catarina
Pinheiro, Manuela
Escudeiro, Carla
Bartosch, Carla
Silva, João
Teixeira, Manuel R.
author_sort Barbosa, Ana
collection PubMed
description SIMPLE SUMMARY: Germline and somatic variant testing of the BRCA1 and BRCA2 genes are important to predict treatment response to PARP inhibitors in ovarian cancer patients. However, germline variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which would be missed by a genetic testing aimed only at treatment decision. We aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of pathology samples of ovarian carcinomas. We identified clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients when compared with genetic testing focused only on BRCA1 and BRCA2. This strategy increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants. ABSTRACT: Since the approval of PARP inhibitors for the treatment of high-grade serous ovarian cancer, in addition to cancer risk assessment, BRCA1 and BRCA2 genetic testing also has therapeutic implications (germline and somatic variants) and should be offered to these patients at diagnosis, irrespective of family history. However, variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which would be missed by a genetic testing aimed only at indication for PARP inhibitor treatment. In this study, we aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of formalin-fixed paraffin-embedded samples from 96 ovarian carcinomas, a strategy that allows the detection of both somatic and germline variants in a single test. In addition to 13.7% of deleterious germline BRCA1/BRCA2 carriers, we identified 7.4% additional patients with pathogenic germline variants in other genes predisposing for ovarian cancer, namely RAD51C, RAD51D, and MSH6, representing 35% of all pathogenic germline variants. We conclude that the strategy of reflex gene-panel tumor testing enables the identification of clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients, which may be valuable information in patients with advanced disease that have run out of approved therapeutic options. Furthermore, this approach increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants.
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spelling pubmed-76507202020-11-10 Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2 Barbosa, Ana Pinto, Pedro Peixoto, Ana Guerra, Joana Pinto, Carla Santos, Catarina Pinheiro, Manuela Escudeiro, Carla Bartosch, Carla Silva, João Teixeira, Manuel R. Cancers (Basel) Article SIMPLE SUMMARY: Germline and somatic variant testing of the BRCA1 and BRCA2 genes are important to predict treatment response to PARP inhibitors in ovarian cancer patients. However, germline variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which would be missed by a genetic testing aimed only at treatment decision. We aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of pathology samples of ovarian carcinomas. We identified clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients when compared with genetic testing focused only on BRCA1 and BRCA2. This strategy increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants. ABSTRACT: Since the approval of PARP inhibitors for the treatment of high-grade serous ovarian cancer, in addition to cancer risk assessment, BRCA1 and BRCA2 genetic testing also has therapeutic implications (germline and somatic variants) and should be offered to these patients at diagnosis, irrespective of family history. However, variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which would be missed by a genetic testing aimed only at indication for PARP inhibitor treatment. In this study, we aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of formalin-fixed paraffin-embedded samples from 96 ovarian carcinomas, a strategy that allows the detection of both somatic and germline variants in a single test. In addition to 13.7% of deleterious germline BRCA1/BRCA2 carriers, we identified 7.4% additional patients with pathogenic germline variants in other genes predisposing for ovarian cancer, namely RAD51C, RAD51D, and MSH6, representing 35% of all pathogenic germline variants. We conclude that the strategy of reflex gene-panel tumor testing enables the identification of clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients, which may be valuable information in patients with advanced disease that have run out of approved therapeutic options. Furthermore, this approach increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants. MDPI 2020-09-30 /pmc/articles/PMC7650720/ /pubmed/33008098 http://dx.doi.org/10.3390/cancers12102834 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barbosa, Ana
Pinto, Pedro
Peixoto, Ana
Guerra, Joana
Pinto, Carla
Santos, Catarina
Pinheiro, Manuela
Escudeiro, Carla
Bartosch, Carla
Silva, João
Teixeira, Manuel R.
Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2
title Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2
title_full Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2
title_fullStr Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2
title_full_unstemmed Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2
title_short Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2
title_sort gene panel tumor testing in ovarian cancer patients significantly increases the yield of clinically actionable germline variants beyond brca1/brca2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650720/
https://www.ncbi.nlm.nih.gov/pubmed/33008098
http://dx.doi.org/10.3390/cancers12102834
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