Abstract
Wilms tumor (WT) is the most frequently diagnosed malignant renal tumor in children. With current treatments, ~90% of children diagnosed with WT survive and generally present with tumors characterized by favorable histology (FHWT), whereas prognosis is poor for the remaining 10% of cases where the tumors are characterized by cellular diffuse anaplasia (DAWT). Relatively few studies have investigated microRNA-related epigenetic regulation and its relationship with altered gene expression in WT. Here, we aim to identify microRNAs differentially expressed in WT and describe their expression in terms of cellular anaplasia, metastasis, and association with the main genetic alterations in WT to identify potential prognostic biomarkers. Expression profiling using TaqMan low-density array was performed in a discovery cohort consisting of four DAWT and eight FHWT samples. Relative quantification resulted in the identification of 109 (48.7%) microRNAs differentially expressed in both WT types. Of these, miR-10a-5p, miR-29a-3p, miR-181a-5p, miR-200b-3p, and miR-218-5p were selected and tested by RT-qPCR on a validation cohort of 53 patient samples. MiR-29a and miR-218 showed significant differences in FHWT with low (P = 0.0018) and high (P = 0.0131) expression, respectively. To discriminate between miRNA expression FHWTs and healthy controls, the receiver operating characteristic (ROC) curves were obtained; miR-29a AUC was 0.7843. Furthermore, low expression levels of miR-29a and miR-200b (P = 0.0027 and P = 0.0248) were observed in metastatic tumors. ROC curves for miR-29a discriminated metastatic patients (AUC = 0.8529) and miR-200b (AUC = 0.7757). To confirm the differences between cases with poor prognosis, we performed in situ hybridization for three microRNAs in five DAWT and 17 FHWT samples, and only significant differences between adjacent tissues and FHWT tumors were found for miR-181a, miR-200b, and miR-218, in both total pixels and nuclear analyses. Analysis of copy number variation in genes showed that the most prevalent alterations were WTX (47%), IGF2 (21%), 1q (36%) gain, 1p36 (16%), and WTX deletion/1q duplicate (26%). The five microRNAs evaluated are involved in the Hippo signaling pathway and participate in Wilms tumor development through their effects on differentiation, proliferation, angiogenesis, and metastasis.
Highlights
Wilms tumor (WT), known as nephroblastoma, is a malignant, solid kidney tumor that affects children
We found that MYCN and WTX (AMER 1) are miR-29a target genes, while MYCN is a target for miR-200b; IGF2 and TP53 are targets for miR218
Structural alterations in numerous genes have been associated with WTs, several cases have been identified where no mutations are present, suggesting that other mechanisms may be involved in WT etiology [20]
Summary
Wilms tumor (WT), known as nephroblastoma, is a malignant, solid kidney tumor that affects children It accounts for ∼8% of all infant neoplasia, and diagnosis usually occurs before the age of five [1]. WT presents three types of cells: blastemal, mesenchymal, and epithelial, with the blastemal type being the most frequent, followed by triphasic, which is characterized by the presence of the three cell types in the same tumor [4]. Each of these cell types has specific characteristics related to WT development, such as chemotherapy-resistant blastemal tumors, with a 5-years survival rate of 65%. The molecular pathways involved in the pathogenesis of this tumor variant remain unclear, there is some evidence indicating that microRNAs (miRNAs) contribute to the development of this neoplasia as epigenetic regulators and that miRNA expression differs between DAWT and FHWT variants [6]
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