Identification of a Novel microRNA Profile in Pediatric Cancer Patients Following Anthracycline Chemotherapy

Abstract

Introduction Anthracycline chemotherapy (AC) can be associated with a progressive decline in left ventricular ejection fraction (LVEF), but the contributory mechanisms remain unclear. While changes in microRNAs (miRs), a key translational control point, have been identified in adult cardiovascular disease, whether and to what degree a shift in miR profiles occurs in pediatric AC patients has not been well studied. The goal of this study was to examine miR profiles (unbiased array) in pediatric AC patients compared to age matched referent normal patients. Hypothesis We hypothesize that pediatric AC patients will express a unique miR profile at initiation and completion of therapy and will be related to LVEF. Methods Serum was collected in pediatric patients (n=12, 13-22 years old) with newly diagnosed malignancy requiring AC within 24-48 hours following initiation of therapy (30-60 mg/m2) and approximately one year after completing maximal therapy. A custom microarray of 84 miRs associated with cardiovascular disease pathways was utilized (RT-qPCR) and indexed to referent normal profiles (n=17, 13-17 years old). LVEF was computed by cardiac MRI. Results LVEF fell from AC initiation at one year following AC (64.28% ± 1.78% vs 57.53% ± 0.95% respectively, p=0.004). Of the 84 miRs profiled, significant shifts in 17 miRs occurred relative to referent normal (p ≤ 0.05) where a nearly equivalent number were upregulated and downregulated (41 vs 59%, respectively). Moreover, the functional domain of miRs associated with myocardial differentiation and development fell by over 3-fold at completion of AC (Figure, p ≤ 0.05). Lastly, miRs-143-3p, -499a-5p, and -142-3p were associated with the fall in LVEF (p ≤ 0.05). Conclusions This study demonstrated for the first time that dynamic changes in miR expression occurs in pediatric cancer patients following AC. These findings suggest that miRs are a potential strategy for early identification of patients most susceptible to LV dysfunction following AC exposure, as well as potential targets for protective therapies.