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

Authors :
Gómez-Vecino A
Corchado-Cobos R
Blanco-Gómez A
García-Sancha N
Castillo-Lluva S
Martín-García A
Mendiburu-Eliçabe M
Prieto C
Ruiz-Pinto S
Pita G
Velasco-Ruiz A
Patino-Alonso C
Galindo-Villardón P
Vera-Pedrosa ML
Jalife J
Mao JH
Macías de Plasencia G
Castellanos-Martín A
Sáez-Freire MDM
Fraile-Martín S
Rodrigues-Teixeira T
García-Macías C
Galvis-Jiménez JM
García-Sánchez A
Isidoro-García M
Fuentes M
García-Cenador MB
García-Criado FJ
García-Hernández JL
Hernández-García MÁ
Cruz-Hernández JJ
Rodríguez-Sánchez CA
García-Sancho AM
Pérez-López E
Pérez-Martínez A
Gutiérrez-Larraya F
Cartón AJ
García-Sáenz JÁ
Patiño-García A
Martín M
Alonso-Gordoa T
Vulsteke C
Croes L
Hatse S
Van Brussel T
Lambrechts D
Wildiers H
Chang H
Holgado-Madruga M
González-Neira A
Sánchez PL
Pérez Losada J
Source :
Cells [Cells] 2023 Jul 27; Vol. 12 (15). Date of Electronic Publication: 2023 Jul 27.
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.

Details

Language :
English
ISSN :
2073-4409
Volume :
12
Issue :
15
Database :
MEDLINE
Journal :
Cells
Publication Type :
Academic Journal
Accession number :
37566035
Full Text :
https://doi.org/10.3390/cells12151956