SHH

Overview

SHH (Sonic Hedgehog) encodes a secreted ligand that activates the Hedgehog signaling pathway by binding to and inhibiting its receptor PTCH1, thereby releasing SMO to activate downstream GLI transcription factors. In cancer, SHH pathway activation drives proliferation particularly in cerebellar granule neuron precursors, forming the molecular basis of the SHH subgroup of medulloblastoma. Germline and somatic alterations in SHH pathway components (PTCH1, SMO, SUFU) define this medulloblastoma subgroup, and SHH itself can be disrupted by structural rearrangements such as fusion genes.

Alterations observed in the corpus

  • Involved in a DNAJB6-SHH fusion transcript in one medulloblastoma case (76-tumor WGS/WES, ICGC cohort); the fused case showed extremely high SHH expression compared to virtually absent expression in 301 other medulloblastomas, suggesting oncogenic activation by juxtaposition to the DNAJB6 amplicon on chr7 PMID:22832583

Cancer types (linked)

  • MB: SHH defines one of the four major molecular subgroups of medulloblastoma; structural rearrangements activating SHH expression are rare but high-impact events within the SHH subgroup PMID:22832583

Co-occurrence and mutual exclusivity

  • DNAJB6: The DNAJB6-SHH fusion arises from an amplicon on chr7, with the first exon of DNAJB6 juxtaposed to SHH creating a fusion transcript PMID:22832583
  • SMO: Co-pathway gene; SMO activating mutations and SHH structural alterations both converge on Hedgehog pathway activation in the SHH medulloblastoma subgroup PMID:22832583
  • SUFU: Co-pathway gene; SUFU loss-of-function and SHH overexpression both activate GLI transcription factors in SHH-subgroup medulloblastoma PMID:22832583

Therapeutic relevance

  • SMO inhibitors (e.g., vismodegib) are approved for SHH-driven tumors and are under evaluation for SHH-subgroup medulloblastoma; SHH pathway gene status (PTCH1, SMO, SUFU, SHH) guides patient selection PMID:22832583

Open questions

  • The frequency and clinical significance of SHH structural rearrangements (vs. upstream pathway mutations) in medulloblastoma require characterization in larger cohorts PMID:22832583

Sources

  • PMID:22832583 — Medulloblastoma WGS/WES, ICGC, 76 tumors (125 total with validation)

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