Prognostic Significance of Mdm2 Gene Expression in Childhood Neuroblastoma

Abstract

Aim: To investigate the association of MDM2 expression at the mRNA levels in neuroblastoma with clinical features and unfavorable disease factors to determine the possibility of it usage as a prognostic marker of neuroblastoma. Materials and Methods: Total RNA and DNA were extracted from tumor tissue samples of total 91 neuroblastoma patients (mean age: 39.45 ± 4.81 months). MDM2 mRNA levels were detected with Q-PCR. TP53 gene deletion was detected with FISH method. MYCN amplification was detected with Q -PCR analysis in fresh tumor samples and FISH in FFPE samples. Results: We investigated the association of MDM2 mRNA expression with clinical outcome in neuroblastoma patients (n = 91). Kaplan — Meier curves showed a significant association of high MDM2 expression with poor event-free survival (p < 0.001). Clinical outcome of patients without MYCN amplification with low MDM2 expression was associated with better event-free survival than with high MDM2 expression (p < 0.001). Overexpression of MDM2 can be used as significant prognostic marker for patient stratification on risk groups and treatment optimization. Conclusion: Our results showed that the high expression of MDM2 at mRNA levels is an important factor of neuroblastoma prognosis. It may be a valuable additional molecular marker in guiding specific therapy in MYCN non-amplified NB patients without TP53 gene deletion.

Targeting anaplastic lymphoma kinase in neuroblastoma

“…Neuroblastoma models in which MYCN is overexpressed in the neural crest lead to neuroblastoma tumor development, that is accelerated by cooperation with other oncogenes and tumor suppressor genes, such as ALK, NF1, TP53, LIN28B and LMO1, driving increased penetrance and earlier onset of neuroblastoma (63)(64)(65)(66)(67)(68). Other factors, which also contribute to neuroblastoma tumorigenesis, are loss of heterozygosity (LOH) for chromosome 14 (14q), loss of NF1 and CDKN2A, amplification of DDX1 and MDM2, aberrant expression of neurotrophin receptors, ganglioside GD2, polycomb complex protein Bmi-1, micro RNAs (miR-10b, miR-29a/b, miR-335), as well as mutations in PHOX2B, ATRX, CHEK2 and BARD1 (53,(69)(70)(71)(72)(73)(74)(75)(76)(77). In addition to protein coding genes, long noncoding RNAs, such as neuroblastoma associated transcript-1 (NBAT-1) and Cancer Susceptibility 15 (CASC15), regulate neuroblastoma tumorigenesis via cell proliferation and neuronal differentiation (78,79).…”

Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

“…MYCN and MYC basally can upregulate TP53 expression, but when overexpressed, either by amplification, translocation, or epigenetically-driven overexpression, these transcription factors can promote MDM2 expression, which ubiquitinates p53 leading to its degradation. MDM2 is overexpressed in pediatric tumors including leukemias [113][114][115] , neuroblastoma [116] , retinoblastoma [117] and associated with poor prognosis and/or treatment resistance [118][119][120][121] , supporting its role in chemoresistant disease. Additional response pathways, such as MEK/ERK activation and NF-kappaB activation, are being studied in pediatric cancers.…”

MiR-137 expression in neuroblastoma: a role in clinical course and outcome.

“…MDM2 mRNA expression level was detected by real-time RT-qPCR using TaqMan primers and probes. MYCN status and MDM2 expression in NB tumor samples were analyzed, as previously described [18]. Results were normalized to relevant controls.…”