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0215U007130,
0113U002151
,
Investigate the genetic and epigenetic mechanisms of neuroblastoma progression and determine the factors of the disease prognosis in children
Khranovska Natalia,
13-02-2015
Ukrainian Research Institute of Oncology and Radiology
Research object - biological material of 91 patients with verified diagnosis of neuroblastoma. Research methods - molecular-genetic, cytogenetic, morphologic, biochemical, statistics. Equipment - instruments for real-time PCR 7300/7500 Real-Time PCR Systems, "AppliedBiosystems", USA; fluorescent microscope Imager.M1 "Axio Zeizz", Germany; scales WPS, centrifuge OPN3-UHL. We established that loss of 17p chromosome region, mapping TP53 gene, was found only in 2.5% of patients with NB. However, dysfunction of signaling pathway p53-MDM2 was detected in 55% of patients due to MDM2 gene overexpression, which is a negative regulator of p53 activity. Elevated levels of MDM2 gene expression were associated with unfavorable course of NB and decline of disease-free survival rate in patients regardless of disease stage and the MYCN gene status. Rates of 2-year disease-free survival of patients with MDM2 gene high expression levels was only 35%, whereas with low expression - 81%. Deletion of 11q23 chromosome region in tumor cells was detected in 20% of patients with NB and was associated with MYCN non-amplified NB and in one case with loss of 17p chromosome region. NB patients with 11q23 deletions without MYCN amplification characterized with poor prognosis of the disease. We also established that microRNA miR-380-5p expression did not have independent effect on the clinical behavior of NB, whereas low expression of miR-885-5p and miR-137 was associated with unfavorable disease course. Thus, low miR-885-5p and miR-137 expression in NB tumor cells correlated with MYCN gene amplification, high levels of MDM2 gene expression and was significantly more common in patients with III-IV stages than in patients with I-II stages of NB. In addition, low miR-137 expression levels were found in 73% of chemotherapy resistant patients with NB. Rates of 2-year disease-free survival of patients with low expression of miR-137 was 41% whereas with high - 67%. No expression of retinoic acid receptor gene (RARB2) was revealed in 21.3% tumor samples of patients with NB. It was established that the level of RARB2 gene expression was significantly higher in tumors with MYCN gene amplification compared with tumors with normal MYCN gene status. Obtained results indicate that dysfunction of p53-MDM2 signaling pathway caused by gene overexpression and downregulation of miR-885-5p, miR-137 are associated with unfavorable course of NB. The aforementioned markers can be recommended for inclusion in the molecular genetic component of NB patients stratification system at risk groups.
Іонкіна Н.В.
Горбач О.І.
Свергун Н.М.
Скачкова О.В.
Храновська Н.М.
2020-04-02
Updated: 2025-12-08
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