Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Gómez-Vecino, Aurora; Corchado-Cobos, Roberto; Blanco-Gómez, Adrián; García-Sancha, Natalia; Castillo-Lluva, Sonia; Martín-García, Ana; Mendiburu-Eliçabe, Marina; Prieto, Carlos; Ruiz-Pinto, Sara; Pita, Guillermo; Velasco-Ruiz, Alejandro; Patino-Alonso, Carmen; Galindo-Villardón, Purificación; Vera-Pedrosa, María Linarejos; Jalife, Jose; Mao, Jian-Hua; Macías de Plasencia, Guillermo; Castellanos-Martín, Andrés; Sáez-Freire, María Del Mar; Fraile-Martín, Susana; Rodrigues-Teixeira, Telmo; García-Macías, Carmen; Galvis-Jiménez, Julie Milena; García-Sánchez, Asunción; Isidoro-García, María; Fuentes, Manuel; García-Cenador, María Begoña; García-Criado, Francisco Javier; García-Hernández, Juan Luis; Hernández-García, María Ángeles; Cruz-Hernández, Juan Jesús; Rodríguez-Sánchez, César Augusto; García-Sancho, Alejandro Martín; Pérez-López, Estefanía; Pérez-Martínez, Antonio; Gutiérrez-Larraya, Federico; Cartón, Antonio J; García-Sáenz, José Ángel; Patiño-García, Ana; Martín, Miguel; Alonso-Gordoa, Teresa; Vulsteke, Christof; Croes, Lieselot; Hatse, Sigrid; Van Brussel, Thomas; Lambrechts, Diether; Wildiers, Hans; Chang, Hang; Holgado-Madruga, Marina; González-Neira, Anna; Sánchez, Pedro L; Pérez Losada, Jesús

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associa...

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Autores:	Gómez-Vecino, Aurora, Corchado-Cobos, Roberto, Blanco-Gómez, Adrián, García-Sancha, Natalia, Castillo-Lluva, Sonia, Martín-García, Ana, Mendiburu-Eliçabe, Marina, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino-Alonso, Carmen, Galindo-Villardón, Purificación, Vera-Pedrosa, María Linarejos, Jalife, Jose, Mao, Jian-Hua, Macías de Plasencia, Guillermo, Castellanos-Martín, Andrés, Sáez-Freire, María Del Mar, Fraile-Martín, Susana, Rodrigues-Teixeira, Telmo, García-Macías, Carmen, Galvis-Jiménez, Julie Milena, García-Sánchez, Asunción, Isidoro-García, María, Fuentes, Manuel, García-Cenador, María Begoña, García-Criado, Francisco Javier, García-Hernández, Juan Luis, Hernández-García, María Ángeles, Cruz-Hernández, Juan Jesús, Rodríguez-Sánchez, César Augusto, García-Sancho, Alejandro Martín, Pérez-López, Estefanía, Pérez-Martínez, Antonio, Gutiérrez-Larraya, Federico, Cartón, Antonio J, García-Sáenz, José Ángel, Patiño-García, Ana, Martín, Miguel, Alonso-Gordoa, Teresa, Vulsteke, Christof, Croes, Lieselot, Hatse, Sigrid, Van Brussel, Thomas, Lambrechts, Diether, Wildiers, Hans, Chang, Hang, Holgado-Madruga, Marina, González-Neira, Anna, Sánchez, Pedro L, Pérez Losada, Jesús
Tipo de recurso:	artículo
Fecha de publicación:	2023
País:	España
Institución:	Instituto de Salud Carlos III (ISCIII)
Repositorio:	Repisalud
Idioma:	inglés
OAI Identifier:	oai:repisalud.isciii.es:20.500.12105/16571
Acceso en línea:	http://hdl.handle.net/20.500.12105/16571
Access Level:	acceso abierto
Palabra clave:	Cardiotoxicity Neoplasms Female Animals Mice Anthracyclines Genetic Markers Antibiotics, Antineoplastic Phenotype

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spelling	Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.Gómez-Vecino, AuroraCorchado-Cobos, RobertoBlanco-Gómez, AdriánGarcía-Sancha, NataliaCastillo-Lluva, SoniaMartín-García, AnaMendiburu-Eliçabe, MarinaPrieto, CarlosRuiz-Pinto, SaraPita, GuillermoVelasco-Ruiz, AlejandroPatino-Alonso, CarmenGalindo-Villardón, PurificaciónVera-Pedrosa, María LinarejosJalife, JoseMao, Jian-HuaMacías de Plasencia, GuillermoCastellanos-Martín, AndrésSáez-Freire, María Del MarFraile-Martín, SusanaRodrigues-Teixeira, TelmoGarcía-Macías, CarmenGalvis-Jiménez, Julie MilenaGarcía-Sánchez, AsunciónIsidoro-García, MaríaFuentes, ManuelGarcía-Cenador, María BegoñaGarcía-Criado, Francisco JavierGarcía-Hernández, Juan LuisHernández-García, María ÁngelesCruz-Hernández, Juan JesúsRodríguez-Sánchez, César AugustoGarcía-Sancho, Alejandro MartínPérez-López, EstefaníaPérez-Martínez, AntonioGutiérrez-Larraya, FedericoCartón, Antonio JGarcía-Sáenz, José ÁngelPatiño-García, AnaMartín, MiguelAlonso-Gordoa, TeresaVulsteke, ChristofCroes, LieselotHatse, SigridVan Brussel, ThomasLambrechts, DietherWildiers, HansChang, HangHolgado-Madruga, MarinaGonzález-Neira, AnnaSánchez, Pedro LPérez Losada, JesúsCardiotoxicityNeoplasmsFemaleAnimalsMiceAnthracyclinesGenetic MarkersAntibiotics, AntineoplasticPhenotypeCardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.Multidisciplinary Digital Publishing Institute (MDPI)Instituto de Salud Carlos IIIUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Ministerio de Ciencia y Competitividad (España)Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)Fundación La Caixa20232023-10-1720232023-07-2720232023-07-27journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/16571reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/165712026-06-12T12:43:37Z
dc.title.none.fl_str_mv	Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.
title	Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.
spellingShingle	Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk. Gómez-Vecino, Aurora Cardiotoxicity Neoplasms Female Animals Mice Anthracyclines Genetic Markers Antibiotics, Antineoplastic Phenotype
title_short	Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.
title_full	Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.
title_fullStr	Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.
title_full_unstemmed	Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.
title_sort	Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.
dc.creator.none.fl_str_mv	Gómez-Vecino, Aurora Corchado-Cobos, Roberto Blanco-Gómez, Adrián García-Sancha, Natalia Castillo-Lluva, Sonia Martín-García, Ana Mendiburu-Eliçabe, Marina Prieto, Carlos Ruiz-Pinto, Sara Pita, Guillermo Velasco-Ruiz, Alejandro Patino-Alonso, Carmen Galindo-Villardón, Purificación Vera-Pedrosa, María Linarejos Jalife, Jose Mao, Jian-Hua Macías de Plasencia, Guillermo Castellanos-Martín, Andrés Sáez-Freire, María Del Mar Fraile-Martín, Susana Rodrigues-Teixeira, Telmo García-Macías, Carmen Galvis-Jiménez, Julie Milena García-Sánchez, Asunción Isidoro-García, María Fuentes, Manuel García-Cenador, María Begoña García-Criado, Francisco Javier García-Hernández, Juan Luis Hernández-García, María Ángeles Cruz-Hernández, Juan Jesús Rodríguez-Sánchez, César Augusto García-Sancho, Alejandro Martín Pérez-López, Estefanía Pérez-Martínez, Antonio Gutiérrez-Larraya, Federico Cartón, Antonio J García-Sáenz, José Ángel Patiño-García, Ana Martín, Miguel Alonso-Gordoa, Teresa Vulsteke, Christof Croes, Lieselot Hatse, Sigrid Van Brussel, Thomas Lambrechts, Diether Wildiers, Hans Chang, Hang Holgado-Madruga, Marina González-Neira, Anna Sánchez, Pedro L Pérez Losada, Jesús
author	Gómez-Vecino, Aurora
author_facet	Gómez-Vecino, Aurora Corchado-Cobos, Roberto Blanco-Gómez, Adrián García-Sancha, Natalia Castillo-Lluva, Sonia Martín-García, Ana Mendiburu-Eliçabe, Marina Prieto, Carlos Ruiz-Pinto, Sara Pita, Guillermo Velasco-Ruiz, Alejandro Patino-Alonso, Carmen Galindo-Villardón, Purificación Vera-Pedrosa, María Linarejos Jalife, Jose Mao, Jian-Hua Macías de Plasencia, Guillermo Castellanos-Martín, Andrés Sáez-Freire, María Del Mar Fraile-Martín, Susana Rodrigues-Teixeira, Telmo García-Macías, Carmen Galvis-Jiménez, Julie Milena García-Sánchez, Asunción Isidoro-García, María Fuentes, Manuel García-Cenador, María Begoña García-Criado, Francisco Javier García-Hernández, Juan Luis Hernández-García, María Ángeles Cruz-Hernández, Juan Jesús Rodríguez-Sánchez, César Augusto García-Sancho, Alejandro Martín Pérez-López, Estefanía Pérez-Martínez, Antonio Gutiérrez-Larraya, Federico Cartón, Antonio J García-Sáenz, José Ángel Patiño-García, Ana Martín, Miguel Alonso-Gordoa, Teresa Vulsteke, Christof Croes, Lieselot Hatse, Sigrid Van Brussel, Thomas Lambrechts, Diether Wildiers, Hans Chang, Hang Holgado-Madruga, Marina González-Neira, Anna Sánchez, Pedro L Pérez Losada, Jesús
author_role	author
author2	Corchado-Cobos, Roberto Blanco-Gómez, Adrián García-Sancha, Natalia Castillo-Lluva, Sonia Martín-García, Ana Mendiburu-Eliçabe, Marina Prieto, Carlos Ruiz-Pinto, Sara Pita, Guillermo Velasco-Ruiz, Alejandro Patino-Alonso, Carmen Galindo-Villardón, Purificación Vera-Pedrosa, María Linarejos Jalife, Jose Mao, Jian-Hua Macías de Plasencia, Guillermo Castellanos-Martín, Andrés Sáez-Freire, María Del Mar Fraile-Martín, Susana Rodrigues-Teixeira, Telmo García-Macías, Carmen Galvis-Jiménez, Julie Milena García-Sánchez, Asunción Isidoro-García, María Fuentes, Manuel García-Cenador, María Begoña García-Criado, Francisco Javier García-Hernández, Juan Luis Hernández-García, María Ángeles Cruz-Hernández, Juan Jesús Rodríguez-Sánchez, César Augusto García-Sancho, Alejandro Martín Pérez-López, Estefanía Pérez-Martínez, Antonio Gutiérrez-Larraya, Federico Cartón, Antonio J García-Sáenz, José Ángel Patiño-García, Ana Martín, Miguel Alonso-Gordoa, Teresa Vulsteke, Christof Croes, Lieselot Hatse, Sigrid Van Brussel, Thomas Lambrechts, Diether Wildiers, Hans Chang, Hang Holgado-Madruga, Marina González-Neira, Anna Sánchez, Pedro L Pérez Losada, Jesús
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 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	Instituto de Salud Carlos III Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) Ministerio de Ciencia y Competitividad (España) Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) Fundación La Caixa
dc.subject.none.fl_str_mv	Cardiotoxicity Neoplasms Female Animals Mice Anthracyclines Genetic Markers Antibiotics, Antineoplastic Phenotype
topic	Cardiotoxicity Neoplasms Female Animals Mice Anthracyclines Genetic Markers Antibiotics, Antineoplastic Phenotype
description	Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.
publishDate	2023
dc.date.none.fl_str_mv	2023 2023-10-17 2023 2023-07-27 2023 2023-07-27
dc.type.none.fl_str_mv	journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	http://hdl.handle.net/20.500.12105/16571
url	http://hdl.handle.net/20.500.12105/16571
dc.language.none.fl_str_mv	Inglés eng
language_invalid_str_mv	Inglés
language	eng
dc.rights.none.fl_str_mv	open access http://purl.org/coar/access_right/c_abf2 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv	info:eu-repo/semantics/openAccess
rights_invalid_str_mv	open access http://purl.org/coar/access_right/c_abf2 Atribución 4.0 Internacional http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Multidisciplinary Digital Publishing Institute (MDPI)
publisher.none.fl_str_mv	Multidisciplinary Digital Publishing Institute (MDPI)
dc.source.none.fl_str_mv	reponame:Repisalud instname:Instituto de Salud Carlos III (ISCIII)
instname_str	Instituto de Salud Carlos III (ISCIII)
reponame_str	Repisalud
collection	Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

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