Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.
Aurora Gómez-VecinoRoberto Corchado-CobosAdrián Blanco-GómezNatalia García-SanchaSonia Castillo-LluvaAna Martín-GarcíaMarina Mendiburu-EliçabeCarlos PrietoSara Ruiz-PintoGuillermo PitaAlejandro Velasco-RuizMaría Carmen Patino-AlonsoM Purificación Galindo-VillardónMaría Linarejos Vera-PedrosaJose JalifeJian-Hua MaoGuillermo Macías de PlasenciaAndrés Castellanos-MartínMaría Del Mar Sáez-FreireSusana Fraile-MartínTelmo Rodrigues-TeixeiraCarmen García-MacíasJulie Milena Galvis-JiménezAsunción García-SánchezMaría Isidoro-GarcíaManuel FuentesMaria-Begoña Garcia-CenadorFrancisco Javier García-CriadoJuan Luis García HernándezMaría Ángeles Hernández-GarcíaJuan Jesús Cruz HernándezCésar Augusto Rodríguez-SánchezAlejandro Martin Martin Garcia-SanchoEstefanía Pérez-LópezPérez-Martínez AntonioFederico Gutiérrez-LarrayaAntonio J CartónJosé Angel García-SaenzAna Patiño-GarcíaMiguel MartinTeresa Alonso-GordoaChristof VulstekeLieselot CroesSigrid HatseThomas Van BrusselDiether LambrechtsHans P M W WildiersHang ChangMarina Holgado-MadrugaAnna González-NeiraPedro Luis SánchezJesús Pérez LosadaPublished in: Cells (2023)
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.
Keyphrases
- genome wide
- copy number
- dna methylation
- magnetic resonance
- newly diagnosed
- oxidative stress
- ejection fraction
- signaling pathway
- end stage renal disease
- heart failure
- prognostic factors
- type diabetes
- crispr cas
- cell proliferation
- drug delivery
- squamous cell carcinoma
- case report
- young adults
- magnetic resonance imaging
- single molecule
- adipose tissue
- skeletal muscle
- hiv infected
- wild type
- stress induced