A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively....

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Autores: Moura, David S., Peña-Chilet, María, Cordero Varela, Juan Antonio, Álvarez-Alegret, Ramiro, Agra-Pujol, Carolina, Izquierdo, Francisco, Ramos, Rafael, Ortega-Medina, Luis, Martín-Dávila, Francisco, Castilla, Carolina, Hernández-León, Carmen Nieves, Romagosa, Cleofe, Vaz Salgado, María Ángeles, Lavernia, Javier, Bagué, Silvia, Mayordomo-Aranda, Empar, Vicioso, Luis, Hernández Barceló, José Emilio, Rubió-Casadevall, Jordi, Juan, Ana de, Fiaño-Valverde, María Concepción, Hindi, Nadia, López-Álvarez, María, Lacerenza, Serena, Dopazo, Joaquín, Gutiérrez, Antonio, Álvarez, Rosa, Valverde, Claudia M., Martínez-Trufero, Javier, Martín-Broto, Javier
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/269160
Acesso em linha:http://hdl.handle.net/10261/269160
Access Level:acceso abierto
Palavra-chave:Gene signature
Predictive biomarkers
Trabectedin
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spelling A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedinMoura, David S.Peña-Chilet, MaríaCordero Varela, Juan AntonioÁlvarez-Alegret, RamiroAgra-Pujol, CarolinaIzquierdo, FranciscoRamos, RafaelOrtega-Medina, LuisMartín-Dávila, FranciscoCastilla, CarolinaHernández-León, Carmen NievesRomagosa, CleofeVaz Salgado, María ÁngelesLavernia, JavierBagué, SilviaMayordomo-Aranda, EmparVicioso, LuisHernández Barceló, José EmilioRubió-Casadevall, JordiJuan, Ana deFiaño-Valverde, María ConcepciónHindi, NadiaLópez-Álvarez, MaríaLacerenza, SerenaDopazo, JoaquínGutiérrez, AntonioÁlvarez, RosaValverde, Claudia M.Martínez-Trufero, JavierMartín-Broto, JavierGene signaturePredictive biomarkersTrabectedinPredictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.This study was funded by the Spanish Group for Research on Sarcoma (GEIS) and partially by PharmaMar. The authors would like to thank the GEIS data center for data management. The authors also thank the donors and the Hospital Universitario Virgen del Rocío—Instituto de Biomedicina de Sevilla Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT17/0015/0041) for part of the human specimens used in this study. David S. Moura is recipient of a Sara Borrell postdoctoral fellowship funded by the National Institute of Health Carlos III (ISCIII) (CD20/00155).John Wiley & SonsGrupo Español de Investigación en SarcomasPharmaMarInstituto de Salud Carlos IIIConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/269160reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1002/1878-0261.12996Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2691602026-05-22T06:33:51Z
dc.title.none.fl_str_mv A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin
title A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin
spellingShingle A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin
Moura, David S.
Gene signature
Predictive biomarkers
Trabectedin
title_short A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin
title_full A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin
title_fullStr A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin
title_full_unstemmed A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin
title_sort A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin
dc.creator.none.fl_str_mv Moura, David S.
Peña-Chilet, María
Cordero Varela, Juan Antonio
Álvarez-Alegret, Ramiro
Agra-Pujol, Carolina
Izquierdo, Francisco
Ramos, Rafael
Ortega-Medina, Luis
Martín-Dávila, Francisco
Castilla, Carolina
Hernández-León, Carmen Nieves
Romagosa, Cleofe
Vaz Salgado, María Ángeles
Lavernia, Javier
Bagué, Silvia
Mayordomo-Aranda, Empar
Vicioso, Luis
Hernández Barceló, José Emilio
Rubió-Casadevall, Jordi
Juan, Ana de
Fiaño-Valverde, María Concepción
Hindi, Nadia
López-Álvarez, María
Lacerenza, Serena
Dopazo, Joaquín
Gutiérrez, Antonio
Álvarez, Rosa
Valverde, Claudia M.
Martínez-Trufero, Javier
Martín-Broto, Javier
author Moura, David S.
author_facet Moura, David S.
Peña-Chilet, María
Cordero Varela, Juan Antonio
Álvarez-Alegret, Ramiro
Agra-Pujol, Carolina
Izquierdo, Francisco
Ramos, Rafael
Ortega-Medina, Luis
Martín-Dávila, Francisco
Castilla, Carolina
Hernández-León, Carmen Nieves
Romagosa, Cleofe
Vaz Salgado, María Ángeles
Lavernia, Javier
Bagué, Silvia
Mayordomo-Aranda, Empar
Vicioso, Luis
Hernández Barceló, José Emilio
Rubió-Casadevall, Jordi
Juan, Ana de
Fiaño-Valverde, María Concepción
Hindi, Nadia
López-Álvarez, María
Lacerenza, Serena
Dopazo, Joaquín
Gutiérrez, Antonio
Álvarez, Rosa
Valverde, Claudia M.
Martínez-Trufero, Javier
Martín-Broto, Javier
author_role author
author2 Peña-Chilet, María
Cordero Varela, Juan Antonio
Álvarez-Alegret, Ramiro
Agra-Pujol, Carolina
Izquierdo, Francisco
Ramos, Rafael
Ortega-Medina, Luis
Martín-Dávila, Francisco
Castilla, Carolina
Hernández-León, Carmen Nieves
Romagosa, Cleofe
Vaz Salgado, María Ángeles
Lavernia, Javier
Bagué, Silvia
Mayordomo-Aranda, Empar
Vicioso, Luis
Hernández Barceló, José Emilio
Rubió-Casadevall, Jordi
Juan, Ana de
Fiaño-Valverde, María Concepción
Hindi, Nadia
López-Álvarez, María
Lacerenza, Serena
Dopazo, Joaquín
Gutiérrez, Antonio
Álvarez, Rosa
Valverde, Claudia M.
Martínez-Trufero, Javier
Martín-Broto, Javier
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Grupo Español de Investigación en Sarcomas
PharmaMar
Instituto de Salud Carlos III
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Gene signature
Predictive biomarkers
Trabectedin
topic Gene signature
Predictive biomarkers
Trabectedin
description Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/269160
url http://hdl.handle.net/10261/269160
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1002/1878-0261.12996
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv John Wiley & Sons
publisher.none.fl_str_mv John Wiley & Sons
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.198674

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