Portal de Periódicos da CAPES

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

2023; Multidisciplinary Digital Publishing Institute; Volume: 12; Issue: 15 Linguagem: Inglês

10.3390/cells12151956

2073-4409

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

Cardiovascular Function and Risk Factors

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.