Scientific publications
- [SOLID TUMOR]
- [ADVANCED THERAPIES FOR PEDIATRIC SOLID TUMORS]
- [CANCER DIVISION]
- [ADVANCED THERAPIES FOR PEDIATRIC SOLID TUMORS]
Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk
Aurora Gómez-Vecino 1 2, Roberto Corchado-Cobos 1 2, Adrián Blanco-Gómez 1 2, Natalia García-Sancha 1 2, Sonia Castillo-Lluva 3 4, Ana Martín-García 2 5, Marina Mendiburu-Eliçabe 1 2, Carlos Prieto 6, Sara Ruiz-Pinto 7, Guillermo Pita 7, Alejandro Velasco-Ruiz 7, Carmen Patino-Alonso 2 8, Purificación Galindo-Villardón 2 8 9, María Linarejos Vera-Pedrosa 10, José Jalife 10, Jian-Hua Mao 11 12, Guillermo Macías de Plasencia 2 5, Andrés Castellanos-Martín 1 2, María Del Mar Sáez-Freire 1 2, Susana Fraile-Martín 13, Telmo Rodrigues-Teixeira 13, Carmen García-Macías 13, Julie Milena Galvis-Jiménez 1 2 14, Asunción García-Sánchez 2 15, María Isidoro-García 2 15 16, Manuel Fuentes 1 2 16 17, María Begoña García-Cenador 2 18, Francisco Javier García-Criado 2 18, Juan Luis García-Hernández 1 2, María Ángeles Hernández-García 19, Juan Jesús Cruz-Hernández 1 2 16 20, César Augusto Rodríguez-Sánchez 1 2 16 20, Alejandro Martín García-Sancho 1 2 19, Estefanía Pérez-López 1 2 19, Antonio Pérez-Martínez 21, Federico Gutiérrez-Larraya 22, Antonio J Cartón 22, José Ángel García-Sáenz 23, Ana Patiño-García 24, Miguel Martín 25, Teresa Alonso-Gordoa 26, Christof Vulsteke 27 28, Lieselot Croes 27 28, Sigrid Hatse 29, Thomas Van Brussel 30 31, Diether Lambrechts 30 31, Hans Wildiers 32, Hang Chang 11 12, Marina Holgado-Madruga 2 33 34, Anna González-Neira 7, Pedro L Sánchez 1 5 16, Jesús Pérez Losada 1 2
Abstract
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.
CITA DEL ARTÍCULO Cells. 2023 Jul 27;12(15):1956. doi: 10.3390/cells12151956.
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