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Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk
- Publication Year :
- 2023
-
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.<br />Ministerio de Ciencia, Innovación y Universidades (España)<br />European Comission<br />Junta de Castilla y León<br />Instituto de Salud Carlos III<br />Ministerio de Economía, Comercio y Empresa (España)<br />Federación Española de Enfermedades Raras<br />Departamento de Defensa (Estados Unidos)<br />National Institutes of Health (Estados Unidos)<br />Universidad de California (Estados Unidos)<br />Instituto Nacional del Cáncer (Estados Unidos)<br />Fundación "la Caixa"<br />Agencia Estatal de Investigación<br />Depto. de Estadística e Investigación Operativa<br />Fac. de Farmacia<br />TRUE<br />pub
Details
- Database :
- OAIster
- Notes :
- application/pdf, 2073-4409, English
- Publication Type :
- Electronic Resource
- Accession number :
- edsoai.on1450544986
- Document Type :
- Electronic Resource