![]() We also identify a number of fusion transcripts in Shh-MB, many of which fall within focally amplified regions and known Shh-MB tumor suppressors. Alterations in these genes are mutually exclusive of each other and found in 18% of Shh-MB tumors. ![]() We find disruption in the cAMP pathway converging on Shh signaling and also detect a cluster of mutations in MYCN which prevent degradation by FBXW7. This non-biased approach to the Shh-MB transcriptome allows us to understand the transcriptional basis and underlying biology of Shh-MB and reveals a previously unsuspected role for many non-coding RNAs. To further understand the biology of Shh-MB and its molecular subtypes, we studied 250 human Shh-MB using strand-specific RNA sequencing with the incorporation of DNA methylation, whole-genome sequencing, and SNP 6.0 copy number analysis. Prior delineation of Shh-MB subtypes used expression microarrays 4, and/or DNA methylation arrays 3, and the biology underlying the differences among the subtypes is poorly understood. The vast difference in the host (babies versus adolescents versus adults) dictates different treatment approaches for different molecular subtypes. ![]() Shh-MB likely comprises four molecular subtypes, Shh-α (adolescents), Shh-β (babies with a poor prognosis), Shh-γ (babies with a good prognosis), and Shh-δ (adults) 3. Shh-MB is clinically heterogeneous with infants, teenagers and adults affected. MB is thought to comprise a group of four molecularly distinct diseases: Wnt, Sonic Hedgehog (Shh), Group 3, and Group 4 2. Current therapy consists of maximal safe resection, radiotherapy in patients over 36 months, and cytotoxic chemotherapy. Medulloblastoma (MB) is the most common malignant pediatric brain tumor and a major cause of morbidity and mortality in the pediatric population 1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. We identify alterations within the cAMP dependent pathway ( GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Nature Communications volume 12, Article number: 1749 ( 2021) The transcriptional landscape of Shh medulloblastoma
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