MicroRNA-125a in Pediatric Medulloblastoma

MicroRNA-125a expression was significantly lower in categories of pediatric Medulloblastoma (MB) patients with worse prognosis, namely LC/A histology and the non-WNT/non-SHH group, suggesting a pathogenetic role. This was highlighted in a recent study by Hemam et al., published in Child's Nervous System.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Children aged 4 to 9 years old show the highest incidence at 44%. Studies of MB have demonstrated that mutations in cell signalling pathways are associated with specific gene expression signatures, which could be detected using relatively simple and widely available techniques. This has led to the introduction of the molecular subtyping in the 2016 World Health Organization (WHO) classification.

According to the 2021 WHO classification of central nervous system (CNS) tumors, MBs are classified based on histopathological features and molecular characteristics. According to molecular characteristics, MB is classified into four groups:

• WNT (wingless-related integration site)-activated MBs
• SHH (sonic hedgehog)-activated MBs, which are separated into TP53-mutant and TP53-wild-types
• Non-WNT/non-SHH MBs, comprising group 3 and group 4, which are listed as provisional variants

The current treatment of MB allows 5-year survival rates ranging between 50 and 90%. This wide range is multifactorial, depending on age at diagnosis, the presence of metastasis at diagnosis, histological pattern, and molecular group. Moreover, current therapeutic modalities come at the expense of life-long morbidity. Therefore, the recent WHO classification has provided a base for novel therapeutic approaches that target cell signalling pathways that are activated aberrantly in MB.

MicroRNAs are small noncoding RNAs that regulate gene expression through sequence-specific binding to 3′-untranslated regions of mRNAs, resulting in translational inhibition or mRNA degradation. Some microRNAs show altered expression in many malignancies, suggesting a critical role played by them in tumorigenesis.

The current study by the Egyptian researchers is the first study to report the expression profile and clinical significance of microRNA-125a in molecular groups of MB and to evaluate its prognostic significance. Fifty MB tumors were collected retrospectively and classified into three molecular groups in the study. The relation between microRNA-125a and different clinicopathological parameters showed a statistically significant relation to histology and molecular groups, while there was no significant relation to age or tumour size. MicroRNA-125a was significantly lower in MB cases with LC/A histology followed by classic histology and then DNMB. It was also significantly lower in the non-WNT/non-SHH molecular group than SHH-activated and TP53-wild-type. The one WNT MB case could not be included in statistical analysis.

It was also found that lower levels of microRNA-125a were associated with parameters described in the literature to have worse prognosis, namely LC/A histology and non-WNT/non-SHH molecular group, suggesting a pathogenetic role for microRNA-125a in these tumors. SHH-activated and TP53-wild-type MB showed 70% 5-year OS, while non-WNT/non-SHH MB showed 55% 5-year OS, consistent with the findings in literature where SHH-activated and TP53-wild-type MB proved to have a favorable outcome, while non‐WNT/non‐SHH tumors had the worst prognosis overall.

The lower levels of microRNA-125a in categories with worse prognosis could be explained by the findings in literature suggesting that it has tumor suppressor function through inhibiting proliferation, invasiveness, and metastasis. Therefore, microRNA-125a could represent a potential target for targeted therapy.

Reference

Hamam, S.M., Abdelzaher, E., Fadel, S.H. et al. Prognostic value of microRNA-125a expression status in molecular groups of pediatric medulloblastoma. Child's Nerv Syst (2023). https://doi.org/10.1007/s00381-023-05899-z