RT Journal Article
T1 Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk
A1 Gómez Vecino, Aurora
A1 Corchado Cobos, Roberto
A1 Blanco Gómez, Adrián
A1 García Sancha, Natalia
A1 Martín García, Ana
A1 Mendiburu-Eliçabe Garganta, Marina
A1 Prieto, Carlos
A1 Ruiz Pinto, Sara
A1 Pita, Guillermo
A1 Velasco Ruiz, Alejandro
A1 Patino Alonso, Carmen
A1 Galindo Villardón, Purificación
A1 Linarejos Vera Pedrosa, María
A1 Jalife, José
A1 Mao, Jian-Hua
A1 Macías de Plasencia, Guillermo
A1 Castellanos Martín, Andrés
A1 Sáez Freire, María del Mar
A1 Fraile Martín, Susana
A1 Rodrigues Teixeira, Telmo
A1 García Macías, Carmen
A1 Galvis Jiménez, Julie Milena
A1 Castillo Lluva, Sonia
A1 García Sánchez, Asunción
A1 Isidoro García, María
A1 Fuentes, Manuel
A1 García Cenador, María Begoña
A1 García Criado, Francisco Javier
A1 García Hernández, Juan Luis
A1 Hernández García, María Ángeles
A1 Cruz Hernández, Juan Jesús
A1 Rodríguez Sánchez, César Augusto
A1 Martín García-Sancho, Alejandro
A1 Pérez López, Estefanía
A1 Pérez Martínez, Antonio
A1 Gutiérrez Larraya, Federico
A1 Cartón, Antonio J.
A1 García Sáenz, José Ángel
A1 Patiño-García, Ana
A1 Martín, Miguel
A1 Alonso Gordoa, Teresa
A1 Vulsteke, Christof
A1 Croes, Lieselot
A1 Hatse, Sigrid
A1 Van Brussel, Thomas
A1 Lambrechts, Diether
A1 Wildiers, Hans
A1 Hang, Chang
A1 Holgado Madruga, Marina
A1 González-Neira, Anna
A1 Sánchez, Pedro L.
A1 Pérez Losada, Jesús
AB 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.
SN 2073-4409
YR 2023
FD 2023-07-27
LK https://hdl.handle.net/20.500.14352/100426
UL https://hdl.handle.net/20.500.14352/100426
LA eng
NO Gómez-Vecino A, Corchado-Cobos R, Blanco-Gómez A, García-Sancha N, Castillo-Lluva S, Martín-García A, et al. Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk. Cells 2023;12:1956. https://doi.org/10.3390/cells12151956.
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Comisión Europea
NO Junta de Castilla y León
NO Instituto de Salud Carlos III
NO Ministerio de Economía, Comercio y Empresa (España)
NO Federación Española de Enfermedades Raras
NO Departamento de Defensa (Estados Unidos)
NO National Institutes of Health (Estados Unidos)
NO Universidad de California (Estados Unidos)
NO Instituto Nacional del Cáncer (Estados Unidos)
NO Fundación "la Caixa"
NO Agencia Estatal de Investigación
DS Docta Complutense
RD 6 oct 2024