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Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors

Testicular germ cell tumors (TGCTs) are the most common cancers in men aged 15–39 years and are divided into two major groups, seminomas and nonseminomas. Novel treatment options are required for these patients, to limit side effects of chemotherapy. We hypothesized that promoter methylation of rele...

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Autores principales: Lobo, João, Constâncio, Vera, Guimarães‐Teixeira, Catarina, Leite‐Silva, Pedro, Miranda‐Gonçalves, Vera, Sequeira, José Pedro, Pistoni, Laura, Guimarães, Rita, Cantante, Mariana, Braga, Isaac, Maurício, Joaquina, Looijenga, Leendert H. J., Henrique, Rui, Jerónimo, Carmen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024740/
https://www.ncbi.nlm.nih.gov/pubmed/33513287
http://dx.doi.org/10.1002/1878-0261.12909
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author Lobo, João
Constâncio, Vera
Guimarães‐Teixeira, Catarina
Leite‐Silva, Pedro
Miranda‐Gonçalves, Vera
Sequeira, José Pedro
Pistoni, Laura
Guimarães, Rita
Cantante, Mariana
Braga, Isaac
Maurício, Joaquina
Looijenga, Leendert H. J.
Henrique, Rui
Jerónimo, Carmen
author_facet Lobo, João
Constâncio, Vera
Guimarães‐Teixeira, Catarina
Leite‐Silva, Pedro
Miranda‐Gonçalves, Vera
Sequeira, José Pedro
Pistoni, Laura
Guimarães, Rita
Cantante, Mariana
Braga, Isaac
Maurício, Joaquina
Looijenga, Leendert H. J.
Henrique, Rui
Jerónimo, Carmen
author_sort Lobo, João
collection PubMed
description Testicular germ cell tumors (TGCTs) are the most common cancers in men aged 15–39 years and are divided into two major groups, seminomas and nonseminomas. Novel treatment options are required for these patients, to limit side effects of chemotherapy. We hypothesized that promoter methylation of relevant homologous recombination (HR) genes might be predictive of response to poly‐ADP ribose polymerase inhibitors (PARPis) in TGCTs. We report a study pipeline combining in silico, in vitro, and clinical steps. By using several databases and in silico tools, we identified BRCA1, RAD51C, PALB2, RAD54B, and SYCP3 as the most relevant genes for further investigation and pinpointed specific CpG sites with pronounced negative correlation to gene expression. Nonseminomas displayed significantly higher methylation levels for all target genes, where increased methylation was observed in patients with more differentiated subtypes and higher disease burden. We independently performed second‐line targeted validation in tissue series from TGCT patients. A moderate and/or strong anti‐correlation between gene expression (assessed by RNA‐sequencing) and promoter methylation (assessed by 450k array) was found, for all of the targets. As a proof of concept, we demonstrated the sensitivity of TGCT cell lines to Olaparib, which associated with differential methylation levels of a subset of targets, namely BRCA1 and RAD51C. Our findings support the use of HR genes promoter methylation as a predictor of the therapeutic response to PARPis in patients with TGCT.
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spelling pubmed-80247402021-04-13 Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors Lobo, João Constâncio, Vera Guimarães‐Teixeira, Catarina Leite‐Silva, Pedro Miranda‐Gonçalves, Vera Sequeira, José Pedro Pistoni, Laura Guimarães, Rita Cantante, Mariana Braga, Isaac Maurício, Joaquina Looijenga, Leendert H. J. Henrique, Rui Jerónimo, Carmen Mol Oncol Research Articles Testicular germ cell tumors (TGCTs) are the most common cancers in men aged 15–39 years and are divided into two major groups, seminomas and nonseminomas. Novel treatment options are required for these patients, to limit side effects of chemotherapy. We hypothesized that promoter methylation of relevant homologous recombination (HR) genes might be predictive of response to poly‐ADP ribose polymerase inhibitors (PARPis) in TGCTs. We report a study pipeline combining in silico, in vitro, and clinical steps. By using several databases and in silico tools, we identified BRCA1, RAD51C, PALB2, RAD54B, and SYCP3 as the most relevant genes for further investigation and pinpointed specific CpG sites with pronounced negative correlation to gene expression. Nonseminomas displayed significantly higher methylation levels for all target genes, where increased methylation was observed in patients with more differentiated subtypes and higher disease burden. We independently performed second‐line targeted validation in tissue series from TGCT patients. A moderate and/or strong anti‐correlation between gene expression (assessed by RNA‐sequencing) and promoter methylation (assessed by 450k array) was found, for all of the targets. As a proof of concept, we demonstrated the sensitivity of TGCT cell lines to Olaparib, which associated with differential methylation levels of a subset of targets, namely BRCA1 and RAD51C. Our findings support the use of HR genes promoter methylation as a predictor of the therapeutic response to PARPis in patients with TGCT. John Wiley and Sons Inc. 2021-03-02 2021-04 /pmc/articles/PMC8024740/ /pubmed/33513287 http://dx.doi.org/10.1002/1878-0261.12909 Text en © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Lobo, João
Constâncio, Vera
Guimarães‐Teixeira, Catarina
Leite‐Silva, Pedro
Miranda‐Gonçalves, Vera
Sequeira, José Pedro
Pistoni, Laura
Guimarães, Rita
Cantante, Mariana
Braga, Isaac
Maurício, Joaquina
Looijenga, Leendert H. J.
Henrique, Rui
Jerónimo, Carmen
Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors
title Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors
title_full Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors
title_fullStr Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors
title_full_unstemmed Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors
title_short Promoter methylation of DNA homologous recombination genes is predictive of the responsiveness to PARP inhibitor treatment in testicular germ cell tumors
title_sort promoter methylation of dna homologous recombination genes is predictive of the responsiveness to parp inhibitor treatment in testicular germ cell tumors
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024740/
https://www.ncbi.nlm.nih.gov/pubmed/33513287
http://dx.doi.org/10.1002/1878-0261.12909
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