Suppressed miR-128-3p combined with TERT overexpression predicts dismal outcomes for neuroblastoma

Article type: Research Article

Authors: Druy, A.E.^{a; b; *} | Tsaur, G.A.^{b; c; d} | Shorikov, E.V.^e | Tytgat, G.A.M.^f | Fechina, L.G.^{b; c}

Affiliations: [a] Laboratory of Molecular Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation | [b] Laboratory of the Cellular Therapy of Oncohematological Disorders, Research Institute of Medical Cell Technologies, Yekaterinburg, Russian Federation | [c] Pediatric Oncology and Hematology Center, Regional Children’s Hospital, Yekaterinburg, Russian Federation | [d] Chair of Laboratory Medicine, Ural State Medical University, Yekaterinburg, Russian Federation | [e] PET-Technology Center of Nuclear Medicine, Yekaterinburg, Russian Federation | [f] Princess Máxima Centre for Pediatric Oncology (PMC), Utrecht, The Netherlands

Correspondence: [*] Corresponding author: A.E. Druy, Laboratory of Molecular Oncology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 3B002, 1, S. Mashela st., Moscow, 117997, Russian Federation. Tel.: +7 9126129392; E-mail: Alexander.Druy@fccho-moscow.ru.

Abstract: BACKGROUND: Molecular and clinical diversity of neuroblastomas is notorious. The activating TERT rearrangements have been associated with dismal prognosis. Suppression of miR-128-3p may complement and enhance the adverse effects of TERT overexpression. OBJECTIVE: The study aimed at evaluation of prognostic significance of the miR-128-3p/TERT expression in patients with primary neuroblastoma. METHODS: RNA samples isolated from fresh-frozen tumor specimens (n= 103) were reverse transcribed for evaluation of miR-128-3p and TERT expression by qPCR. The normalized expression levels were tested for correlations with the event-free survival (EFS). ROC-analysis was used to establish threshold expression levels (TLs) for the possible best prediction of the outcomes. The median follow-up was 57 months. RESULTS: Both TERT overexpression and miR-128-3p downregulation were independently associated with superior rates of adverse events (p= 0.027, TL =-2.32 log10 and p= 0.080, TL =-1.33 log10, respectively). The MYCN single-copy patients were stratified into groups based on the character of alterations in expression of the studied transcripts. Five-year EFS in the groups of patients with elevated TERT/normal miR-128-3p expression and normal TERT/reduced miR-128-3p expression were 0.74 ± 0.08 and 0.60 ± 0.16, respectively. The patients with elevated TERT/reduced miR-128-3p expression had the worst outcomes, with 5-year EFS of 0.40 ± 0.16 compared with 0.91 ± 0.06 for the patients with unaltered levels of both transcripts (p< 0.001). Cumulative incidence of relapse/progression for the groups constituted 0.23 ± 0.08, 0.40 ± 0.16, 0.60 ± 0.16 and 0.09 ± 0.06, respectively. Moreover, the loss of miR-128-3p was qualified as independent adverse predictor which outperformed the conventional clinical and genetic risk factors in the multivariate Cox regression model of EFS. CONCLUSIONS: Combined expression levels of miR-128-3p and TERT represent a novel prognostic biomarker for neuroblastoma.

Keywords: Neuroblastoma, miR-128-3p, expression, prognosis

DOI: 10.3233/CBM-210414

Journal: Cancer Biomarkers, vol. 34, no. 4, pp. 661-671, 2022