HMGA2 overexpression predicts relapse susceptibility of blastemal Wilms tumor patients
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Lourdes Hontecillas-Prieto1,*, Daniel J. García-Domínguez1,*, Rosa García-Mejías1, Gema L. Ramírez-Villar2, Carmen Sáez1,** and Enrique de Álava1,**
1Institute of Biomedicine of Seville (IBiS), Pathology Unit, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, CIBERONC, Seville, Spain
2Pediatric Oncology Unit, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
*These authors have contributed equally to this work as first authors
**These authors have contributed equally to this work as senior authors
Lourdes Hontecillas-Prieto, email: firstname.lastname@example.org
Daniel J. García-Domínguez, email: email@example.com
Enrique de Álava, email: firstname.lastname@example.org
Carmen Sáez, email: email@example.com
Keywords: Wilms tumors; embryonic stem cell markers; HMGA2; blastemal stratification
Received: August 24, 2017 Accepted: December 04, 2017 Published: December 14, 2017
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.
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