# The transcriptional landscape of Shh medulloblastoma

## TL;DR

This study explores the genetic and molecular diversity of Sonic hedgehog medulloblastoma, identifying new non-coding RNA roles and key pathways for potential treatment.

## Contribution

The study reveals new insights into non-coding RNA transcripts and molecular convergence in Sonic hedgehog medulloblastoma subtypes.

## Key findings

- Non-coding RNA transcripts play a significant role in Sonic hedgehog medulloblastoma.
- 18% of tumors have genetic events affecting MYCN abundance or stability.
- Fusions in GLI2 and loss-of-function fusions in PTCH1, SUFU, and NCOR1 are identified.

## Abstract

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. 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. 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. 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. 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.

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.