Identification of Let-7 miRNA Activity as a Prognostic Biomarker of SHH Medulloblastoma

SIMPLE SUMMARY: Medulloblastoma is the most common malignant pediatric brain tumor. It can be divided into four molecular subgroups with clear biological and clinical differences: Group 3, Group 4, SHH, and WNT. The Group 3 subgroup has the lowest overall survival rate, and the WNT subgroup has the highest. It is known that MYCN and let-7 play a critical role in medulloblastoma tumorigenesis and progression. By integrating multi-omics data, including gene expression, methylation, copy number variation, and miRNA expression, we further divided the SHH subgroup according to MYCN expression and let-7 activity and found that the combination of high MYCN expression and high let-7 activity is associated with worse overall survival. ABSTRACT: Medulloblastoma (MB) is the most common pediatric embryonal brain tumor. The current consensus classifies MB into four molecular subgroups: sonic hedgehog-activated (SHH), wingless-activated (WNT), Group 3, and Group 4. MYCN and let-7 play a critical role in MB. Thus, we inferred the activity of miRNAs in MB by using the ActMiR procedure. SHH-MB has higher MYCN expression than the other subgroups. We showed that high MYCN expression with high let-7 activity is significantly associated with worse overall survival, and this association was validated in an independent MB dataset. Altogether, our results suggest that let-7 activity and MYCN can further categorize heterogeneous SHH tumors into more and less-favorable prognostic subtypes, which provide critical information for personalizing treatment options for SHH-MB. Comparing the expression differences between the two SHH-MB prognostic subtypes with compound perturbation profiles, we identified FGFR inhibitors as one potential treatment option for SHH-MB patients with the less-favorable prognostic subtype.