Abstract
Wilms tumor (WT) is an embryonal malignant neoplasm of the kidney that accounts for 6–7% of all childhood cancers. WT seems to derive from multipotent embryonic renal stem cells that have failed to differentiate properly. Since mechanisms underlying WT tumorigenesis remain largely unknown, the aim of this study was to explore the expression of embryonic stem cell (ESC) markers in samples of WT patients after chemotherapy treatment SIOP protocol, as the gene expression patterns of ESC are like those of most cancer cells. We found that expression of ESC markers is heterogeneous, and depends on histological WT components. Interestingly, among ESC markers, HMGA2 was expressed significantly stronger in the blastemal component than in the stromal and the normal kidney. Moreover, two subsets of patients of WT blastemal type were identified, depending on the expression levels of HMGA2. High HMGA2 expression levels were significantly associated with a higher proliferation rate (p=0.0345) and worse patient prognosis (p=0.0289). The expression of HMGA2 was a stage-independent factor of clinical outcome in blastemal WT patients. Our multivariate analyses demonstrated the association between LIN28B–LET7A–HMGA2 expression, and the positive correlation between HMGA2 and SLUG expression (p=0.0358) in blastemal WT components. In addition, patients with a poor prognosis and high HMGA2 expression presented high levels of MDR3 (multidrug resistance transporter). Our findings suggest that HMGA2 plays a prominent role in the pathogenesis of a subset of blastemal WT, strongly associated with relapse and resistance to chemotherapy.
Highlights
Wilms tumor (WT) or nephroblastoma is the most common pediatric renal tumor and represents 6% of all childhood cancers
We found that expression of Kruppel Like Factor 4 (KLF4), NOTCH1, and Octamer-binding Transcription factor 3/4 (OCT3/4) was significantly lower in WT samples than in their normal kidney counterparts
NOTCH1 and SRY-Box 9 (SOX9) were expressed in the epithelial WT component with a significant correlation (p=0.0061) between them
Summary
Wilms tumor (WT) or nephroblastoma is the most common pediatric renal tumor and represents 6% of all childhood cancers. Chemotherapy, and/or radiotherapy has greatly improved the prognosis of children with WT and the 5-year diseasefree survival rate has increased from 30% to 85% [2,3,4,5,6]. In Europe, SIOP delays nephrectomy for 4–6 weeks, favouring upfront chemotherapy to minimize complications of surgery and tumor spillage [14, 16]. Different, both treatment approaches have shown almost equivalent clinical outcomes [15, 17,18]
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