Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk

[EN]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 ass...

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Authors: Gómez-Vecino, Aurora, Corchado-Cobos, Roberto, Blanco-Gómez, Adrián, García-Sancha, Natalia, Castillo-Lluva, Sonia, García Martín, Ana María, Mendiburu-Eliçabe, Marina, Prieto, Carlos, Ruiz-Pinto, Sara, Pita, Guillermo, Velasco-Ruiz, Alejandro, Patino Alonso, María Carmen, Galindo Villardón, Purificación, Vera-Pedrosa, María Linarejos, Jalife, José, 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, Hang, Chang, Holgado Madruga, Marina, González-Neira, Anna, Sánchez, Pedro L., Pérez Losada, Jesús
Format: article
Status:Published version
Publication Date:2023
Country:España
Institution:Universidad de Salamanca (USAL)
Repository:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:dnet:gredos______::6867a8dad167b55fc20939b7e8b2f629
Online Access:http://hdl.handle.net/10366/170983
Access Level:Open access
Keyword:anthracyclines
cardiotoxicity
complex genetic disease
intermediate molecular phenotypes
quantitative trait loci
Genetic Predisposition to Disease
Anthracyclines
Animals
Genetic Loci
3209 Farmacología
antraciclinas
animales
predisposición genética a la enfermedad
sitios genéticos
Description
Summary:[EN]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.

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