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Medulloblastoma, WNT-activated/SHH-activated: clinical impact of molecular analysis and histogenetic evaluation

Eduardo Cambruzzi1,2,3,4,5

  • 1Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. dudacambruzzi@yahoo.com.br.

Child'S Nervous System : Chns : Official Journal of the International Society for Pediatric Neurosurgery
|March 28, 2018
PubMed
Abstract

Insights

Medulloblastoma (MDB) is a pediatric brain tumor with varied prognoses. Molecular subgrouping, including WNT-activated and SHH-activated MDB, aids in predicting outcomes and guiding treatment strategies.

Area of Science:

  • Pediatric oncology
  • Neuro-oncology
  • Cancer genomics

Background:

  • Medulloblastoma (MDB) is a common pediatric embryonal brain tumor originating in the cerebellum.
  • Prognosis varies based on stage, histology, and molecular classification.
  • The World Health Organization (WHO) 2016 classification defines four main MDB molecular groups: WNT-activated, SHH-activated, Group 3, and Group 4.

Purpose of the Study:

  • To outline the molecular classification of medulloblastoma (MDB) according to WHO 2016 guidelines.
  • To describe the distinct characteristics and clinical implications of WNT-activated and SHH-activated MDB subtypes.
  • To highlight key genetic mutations and immunohistochemical markers associated with MDB molecular groups.

Main Methods:

  • Review of WHO 2016 Classification of Tumors of the Central Nervous System (CNS).
  • Analysis of genetic mutations (e.g., CTNNB1, TP53, MYCN, GLI2, PTCH1) and chromosomal abnormalities (e.g., monosomy 6, 17p loss, 10q loss).
  • Immunohistochemistry (IHC) for beta-catenin, GAB1, and YAP1 expression.

Main Results:

  • WNT-activated MDB (10% of cases) is linked to monosomy 6, CTNNB1, DDX3X, TP53 mutations, and beta-catenin nuclear expression, generally indicating a better prognosis.
  • SHH-activated MDB has variable outcomes; TP53-mutant subtypes may show anaplastic patterns with MYCN/GLI2 amplification, while TP53-wildtype subtypes often present with desmoplastic/nodular morphology.
  • Gene expression and methylation profiling are definitive for molecular subtyping; GAB1 IHC indicates SHH activation or PTCH mutation, and YAP1 IHC is positive in WNT- and SHH-activated MDB.

Conclusions:

  • Molecular subgrouping is critical for understanding medulloblastoma (MDB) heterogeneity and patient outcomes.
  • WNT- and SHH-activated MDB exhibit distinct genetic profiles and clinical behaviors.
  • Specific genetic mutations and IHC markers aid in the diagnosis and classification of MDB subtypes.
Keywords:
Central nervous system tumorsEmbryonal neuroepithelial tumorMedulloblastomaPrognosisSHH-activatedWNT-activated

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