Identification of Let-7 miRNA Activity as a Prognostic Biomarker of SHH Medulloblastoma
CANCERS(2022)
摘要
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. 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.
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关键词
miRNA, medulloblastoma, prognostic, MYCN, let-7, sonic hedgehog, ActMiR
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