Definition
- Essential:
- A medulloblastoma AND
- Mutant TP53 gene AND
- SHH pathway activation OR
- A DNA methylation profile aligned with SHH-activated medulloblastoma
Numbers
- 30% of all medulloblastomas
- Found in children aged 4-17 years (ave 15yrs).
- M>F = 2:1
- Bimodal age distribution
- Infants (<3 years of age)
- Adults (>17 years of age)
- Carries a higher mutational burden,
- A higher prevalence of SHH pathway- associated mutations (including higher incidence of PTCH1 and SMO alterations)
- A more expansive list of chromatin modifier mutations (bromodomain and PHD finger containing 1 (BRPF1) and CREB binding protein (CREBBP))
- TERT promoter point mutation (100%)
CNS WHO grading
- Grade 4
Origin
- ATOH1-positive external cerebellar granule neuron precursors
Localization (specific data on TP53 mutant vs wildtype are not present)
- Young children: rostral cerebellar hemispheres,
- Older children: vermis
Mechanism
- Inactivating mutations in Patched 1 (Ptch1), the antagonizing receptor for SHH ligand → aberrant activation of the SHH pathway, with increased transcription of Hh pathway target genes, including Ptch2, Gli1, and Gli2
- Inactivated signalling (left) occurs in the absence of SHH ligands, wherein PTCH inhibits SMO resulting in GLI1 sequestration in the cytoplasm by SuFu.
- In the presence of SHH (right), PTCH suppression of SMO is abrogated, resulting in the nuclear accumulation of GLI1 and activation of target genes that promote several oncogenic properties in tumor cells.
Histological subtype
- Classic
- Uncommon high-risk tumour
- Large cell / anaplastic
- 60% of Medulloblastoma, SHH activated
- High-risk tumour; prevalent in children aged 7-17 years
- Desmoplastic / nodular (very rare)
- 40% of Medulloblastoma, SHH activated
- Tumour of uncertain clinicopathological significance
Molecular subtypes
Immunophenotype same for all medulloblastoma
- Positive:
- SHH: can use the following as surrogate marker
- GAB1
- Anti-GAB1 antibody labelled only tumours with an SHH-activated profile or PTCH1 (patched-1 protein) mutation,
- TNFRSF16
- SFRP1
- YAP1 antibody labelled tumour cells in both WNT-activated and SHH-activated medulloblastomas, but not non-WNT/ non-SHH medulloblastomas.
- Plus other immunophenotype listed above
Genetic profile
- Amplification of
- GLI2
- MYCN
- SHH
- Absent mutations in
- PTCH1
- SUFU (suppressor of fused homologue)
- SMO (smoothened homologue)
- Chromosomal alterations
- Loss
- 9q
- 10q
- 14q
- 17p
- Gain
- 2
- 9p
- TERT promoter point mutation 21%
- Point mutation of TP53 due to chromothripsis (shattering and rearrangement of chromosome)
- Associated with Gorlin syndrome (naevoid basal cell carcinoma syndrome)
- Due to mutation of
- PTCH1 (56%)
- SUFU: rarer as a cause
- Characterized by
- Multiple basal cell carcinomas of the skin
- Odontogenic jaw keratocysts
- Medulloblastoma
- Developmental abnormalities
Prognosis
- Poor outcome
- 5-year overall survival: 41% for those with a TP53-mutant tumour
- TP53 mutation will only affect prognosis in the SHH activated group of medulloblastoma but not affect prognosis in WNT activated medulloblastomas
- Small-molecule inhibitors that act on the SMO receptor have been shown to be effective in some medulloblastomas with hedgehog activation
- SMO inhibitors
- Adults with SHH-activated medulloblastoma are more likely to harbour activating alterations in PTCH1 or SMO resulting in tumours sensitive to SMO inhibitors,
- SHH activated medulloblastomas from infants and children (including SHH-activated and TP53-mutant tumours) often contain downstream alterations in SUFU, GLI2, and MYCN that are refractory to these pharmacological agents.
- It has been suggested that DNA-damaging alkylating agents and radiation should be avoided whenever possible when treating patients with a germline TP53 mutation
- Local relapses in SHH-MB tumour
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