Medulloblastoma, SHH-Activated - Disorder Mechanisms

🏷

Classifications

Harrison's Chapter

ICD-O Morphology

◆

Subtypes

2

SHH-Activated, TP53-Wildtype Medulloblastoma

The majority of SHH-activated medulloblastomas retain wildtype TP53. Prognosis is intermediate between WNT-activated (best) and Group 3 (worst), with approximately 70-80% long-term survival. May respond to SHH pathway inhibitors.

Show evidence (1 reference)

PMID:35489737 SUPPORT Human Clinical

"Recent WHO (2021) guidelines stratified MB into four molecular subgroups with four and eight further subgroups for SHH and non-WNT/non-SHH MB, respectively."

Supports the WHO 2021 stratification of SHH-activated medulloblastoma into TP53-defined molecular subtypes.

SHH-Activated, TP53-Mutant Medulloblastoma

Approximately 10-15% of SHH-activated medulloblastomas harbor TP53 mutations, often associated with Li-Fraumeni syndrome (germline TP53 mutation). These tumors have significantly worse prognosis (approximately 40-50% survival), often show large cell/anaplastic histology and chromothripsis.

Show evidence (1 reference)

PMID:35489737 SUPPORT Human Clinical

"recent molecular analyses have subdivided SHH MB into several subtypes with distinct characteristics such as age, TP53 mutation, MYC amplification, presence of metastases, TERT promoter alterations, PTEN loss, and other chromosomal alterations as well as SHH pathway-related gene mutations."

Directly supports TP53 mutation as a defining feature of a high-risk SHH-activated medulloblastoma subtype.

⚙

Pathophysiology

3

SHH Pathway Activation

The SHH pathway is activated through loss of function mutations in PTCH1 (receptor that normally inhibits SMO), activating mutations in SMO, loss of SUFU (negative regulator), or amplification of downstream effectors (GLI2, MYCN). This leads to constitutive activation of GLI transcription factors.

cerebellar granule cell link

smoothened signaling pathway link ↑ INCREASED

cerebellum link

Downstream

GLI Transcription Factor Activation Pathway activation leads to GLI nuclear translocation

Show evidence (1 reference)

PMID:35489737 SUPPORT

"SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."

This abstract explicitly states that SHH tumors have GLI1/GLI2/SUFU/PTCH1 alterations that constitutively activate SHH signaling.

GLI Transcription Factor Activation

Activated SMO leads to nuclear translocation of GLI transcription factors (GLI1, GLI2) which activate target genes including PTCH1 (feedback), GLI1, MYCN, CCND1, and BCL2. GLI2 amplification can drive pathway activation independently of upstream components.

positive regulation of transcription by RNA polymerase II link ↑ INCREASED

Downstream

Cerebellar Granule Cell Proliferation GLI targets drive proliferation of cerebellar progenitors

Show evidence (1 reference)

PMID:35489737 SUPPORT Human Clinical

"SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."

Directly supports activation of GLI1 and GLI2 transcription factors as the molecular endpoint of SHH pathway activation in this tumor.

Cerebellar Granule Cell Proliferation

SHH signaling normally controls proliferation of granule neuron precursors in the external granule layer during cerebellar development. Constitutive pathway activation leads to unchecked proliferation of these precursors, resulting in tumor formation.

cerebellar granule cell link

cell population proliferation link ↑ INCREASED cerebellum development link ⚠ ABNORMAL

Show evidence (1 reference)

PMID:10027293 SUPPORT Model Organism

"Sonic hedgehog (Shh), which is made by Purkinje cells, regulates the division of granule cell precursors (GCPs)."

Foundational mouse evidence that SHH signaling regulates cerebellar granule cell precursor proliferation, the developmental program hijacked in SHH-activated medulloblastoma.

✶

Histopathology

1

Malignant Pediatric Brain Tumor VERY_FREQUENT

Medulloblastoma is the most common malignant brain tumor of childhood.

Show evidence (1 reference)

PMID:41544627 SUPPORT

"Medulloblastoma, the most common malignant brain tumor of childhood, exhibits"

Abstract states medulloblastoma is the most common malignant brain tumor of childhood.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

4

Digestive 1

Nausea and Vomiting VERY_FREQUENT Vomiting (HP:0002013)

Head and Neck 1

Macrocephaly FREQUENT Macrocephaly (HP:0000256)

Nervous System 2

Headache VERY_FREQUENT Headache (HP:0002315)

Ataxia VERY_FREQUENT Ataxia (HP:0001251)

🧬

Genetic Associations

7

PTCH1 (Somatic/Germline Mutation)

Show evidence (2 references)

PMID:35489737 SUPPORT Human Clinical

"SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."

Directly supports PTCH1 as a recurrently mutated gene in SHH-activated medulloblastoma.

PMID:26169613 SUPPORT Human Clinical

"Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS"

Provides clinical evidence that PTCH1 LOH defines a clinically meaningful SHH-MB subgroup with distinct vismodegib response.

SMO (Somatic Mutation)

SUFU (Somatic/Germline Mutation)

Show evidence (1 reference)

PMID:35489737 SUPPORT Human Clinical

"SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."

Directly supports SUFU as a recurrently mutated SHH pathway gene in SHH-activated medulloblastoma.

GLI2 (Amplification)

Show evidence (1 reference)

PMID:35489737 SUPPORT Human Clinical

"SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."

Directly supports GLI2 as a recurrently altered SHH pathway gene in SHH-activated medulloblastoma.

MYCN (Amplification)

Show evidence (1 reference)

PMID:35489737 PARTIAL Human Clinical

"Originally, the presence of TP53 gene alterations and/or MYC amplifications was considered the most reliable prognostic factor."

Supports the prognostic importance of MYC-family amplification in SHH medulloblastoma literature, but the abstract does not distinguish MYCN specifically.

TP53 (Somatic/Germline Mutation)

Show evidence (1 reference)

PMID:35489737 SUPPORT Human Clinical

"Originally, the presence of TP53 gene alterations and/or MYC amplifications was considered the most reliable prognostic factor."

Directly supports TP53 mutation status as a key prognostic marker in SHH-activated medulloblastoma.

TERT (Promoter Mutation)

Show evidence (1 reference)

PMID:35489737 SUPPORT Human Clinical

"recent molecular analyses have subdivided SHH MB into several subtypes with distinct characteristics such as age, TP53 mutation, MYC amplification, presence of metastases, TERT promoter alterations, PTEN loss, and other chromosomal alterations as well as SHH pathway-related gene mutations."

Supports TERT promoter mutations as a recurrent molecular alteration that defines a SHH-activated medulloblastoma subtype.

💊

Treatments

4

Surgical Resection

Action: surgical procedure MAXO:0000004

Maximal safe resection is first-line treatment. Lateral/hemispheric location often allows gross total resection. Extent of resection is prognostic.

Show evidence (1 reference)

PMID:40199599 SUPPORT Human Clinical

"Gross total resection was achieved, and after a short recovery period, adjuvant craniospinal irradiation plus chemotherapy is started."

Directly supports gross total surgical resection followed by adjuvant therapy as the standard care for medulloblastoma.

Craniospinal Irradiation

Action: radiation therapy MAXO:0000014

Craniospinal irradiation is standard for children >3 years due to risk of leptomeningeal spread. Radiation is typically avoided in infants (<3 years) due to severe neurocognitive effects.

Show evidence (1 reference)

PMID:40199599 SUPPORT Human Clinical

"Gross total resection was achieved, and after a short recovery period, adjuvant craniospinal irradiation plus chemotherapy is started."

Directly supports adjuvant craniospinal irradiation as part of standard medulloblastoma management.

Chemotherapy

Action: chemotherapy MAXO:0000647

Multi-agent chemotherapy is standard. For infants, intensive chemotherapy regimens aim to delay or avoid radiation. Standard agents include cisplatin, vincristine, cyclophosphamide, and lomustine.

Show evidence (1 reference)

PMID:40199599 SUPPORT Human Clinical

"adjuvant craniospinal irradiation plus chemotherapy is started."

Directly supports adjuvant chemotherapy alongside radiation as part of standard medulloblastoma therapy.

SHH Pathway Inhibitors (Vismodegib/Sonidegib)

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: vismodegib ↗ sonidegib ↗

SMO inhibitors show activity in recurrent SHH-activated medulloblastoma with upstream pathway mutations (PTCH1). Resistance develops through SMO mutations or pathway activation downstream of SMO (GLI amplification, SUFU mutations). Growth plate toxicity limits use in children.

Show evidence (2 references)

PMID:26169613 SUPPORT Human Clinical

"Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH-MB."

Phase II trial evidence directly supports vismodegib as targeted therapy for SHH-activated medulloblastoma.

PMID:26169613 SUPPORT Human Clinical

"Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses."

Supports the mechanism of vismodegib resistance through downstream SMO pathway mutations (GLI/SUFU).

{ }

Source YAML

click to show

name: Medulloblastoma, SHH-Activated
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-09T19:42:12Z'
description: >-
  Medulloblastoma, SHH-activated, is a molecularly defined subgroup of medulloblastoma
  characterized by activation of the Sonic Hedgehog (SHH) signaling pathway. This
  subgroup represents approximately 30% of medulloblastomas and shows a bimodal age
  distribution, occurring in infants (<3 years) and adults (>16 years) more than
  children. SHH-activated tumors arise from cerebellar granule neuron precursors in
  the external granule layer and can result from mutations in PTCH1, SMO, SUFU, or
  GLI2, as well as MYCN or GLI2 amplification. Under WHO 2021 classification, this
  subgroup is further stratified by TP53 mutation status: SHH-activated and TP53-mutant
  tumors have significantly worse prognosis than TP53-wildtype tumors. SHH pathway
  inhibitors (vismodegib, sonidegib) show activity but resistance develops.
categories:
- Central Nervous System Neoplasm
- Pediatric Brain Tumor
- Adult Brain Tumor
- Molecularly Defined Tumor
- Embryonal Tumor
parents:
- medulloblastoma
has_subtypes:
- name: SHH-Activated, TP53-Wildtype Medulloblastoma
  description: >-
    The majority of SHH-activated medulloblastomas retain wildtype TP53. Prognosis
    is intermediate between WNT-activated (best) and Group 3 (worst), with
    approximately 70-80% long-term survival. May respond to SHH pathway inhibitors.
  evidence:
  - reference: PMID:35489737
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent WHO (2021) guidelines stratified MB into four molecular subgroups with four and eight further subgroups for SHH and non-WNT/non-SHH MB, respectively."
    explanation: Supports the WHO 2021 stratification of SHH-activated medulloblastoma into TP53-defined molecular subtypes.
- name: SHH-Activated, TP53-Mutant Medulloblastoma
  description: >-
    Approximately 10-15% of SHH-activated medulloblastomas harbor TP53 mutations,
    often associated with Li-Fraumeni syndrome (germline TP53 mutation). These
    tumors have significantly worse prognosis (approximately 40-50% survival),
    often show large cell/anaplastic histology and chromothripsis.
  evidence:
  - reference: PMID:35489737
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recent molecular analyses have subdivided SHH MB into several subtypes with distinct characteristics such as age, TP53 mutation, MYC amplification, presence of metastases, TERT promoter alterations, PTEN loss, and other chromosomal alterations as well as SHH pathway-related gene mutations."
    explanation: Directly supports TP53 mutation as a defining feature of a high-risk SHH-activated medulloblastoma subtype.
pathophysiology:
- name: SHH Pathway Activation
  description: >-
    The SHH pathway is activated through loss of function mutations in PTCH1
    (receptor that normally inhibits SMO), activating mutations in SMO, loss of
    SUFU (negative regulator), or amplification of downstream effectors (GLI2,
    MYCN). This leads to constitutive activation of GLI transcription factors.
  evidence:
  - reference: PMID:35489737
    reference_title: "Molecular Stratification of Medulloblastoma: Clinical Outcomes and Therapeutic Interventions."
    supports: SUPPORT
    snippet: "SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."
    explanation: This abstract explicitly states that SHH tumors have GLI1/GLI2/SUFU/PTCH1 alterations that constitutively activate SHH signaling.
  cell_types:
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  biological_processes:
  - preferred_term: smoothened signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007224
      label: smoothened signaling pathway
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  downstream:
  - target: GLI Transcription Factor Activation
    description: Pathway activation leads to GLI nuclear translocation
    evidence:
    - reference: PMID:35489737
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."
      explanation: Supports the causal link from upstream SHH pathway lesions to constitutive GLI activation in SHH-activated medulloblastoma.
- name: GLI Transcription Factor Activation
  description: >-
    Activated SMO leads to nuclear translocation of GLI transcription factors
    (GLI1, GLI2) which activate target genes including PTCH1 (feedback), GLI1,
    MYCN, CCND1, and BCL2. GLI2 amplification can drive pathway activation
    independently of upstream components.
  evidence:
  - reference: PMID:35489737
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."
    explanation: Directly supports activation of GLI1 and GLI2 transcription factors as the molecular endpoint of SHH pathway activation in this tumor.
  biological_processes:
  - preferred_term: positive regulation of transcription by RNA polymerase II
    modifier: INCREASED
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
  downstream:
  - target: Cerebellar Granule Cell Proliferation
    description: GLI targets drive proliferation of cerebellar progenitors
    evidence:
    - reference: PMID:10027293
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Treatment of GCPs with Shh prevents differentiation and induces a potent, long-lasting proliferative response."
      explanation: Mouse cerebellar granule cell precursor data supports the link between SHH/GLI pathway activation and granule cell proliferation in the developing cerebellum.
- name: Cerebellar Granule Cell Proliferation
  description: >-
    SHH signaling normally controls proliferation of granule neuron precursors
    in the external granule layer during cerebellar development. Constitutive
    pathway activation leads to unchecked proliferation of these precursors,
    resulting in tumor formation.
  evidence:
  - reference: PMID:10027293
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Sonic hedgehog (Shh), which is made by Purkinje cells, regulates the division of granule cell precursors (GCPs)."
    explanation: Foundational mouse evidence that SHH signaling regulates cerebellar granule cell precursor proliferation, the developmental program hijacked in SHH-activated medulloblastoma.
  cell_types:
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: cerebellum development
    modifier: ABNORMAL
    term:
      id: GO:0021549
      label: cerebellum development
histopathology:
- name: Malignant Pediatric Brain Tumor
  finding_term:
    preferred_term: Medulloblastoma
    term:
      id: NCIT:C3222
      label: Medulloblastoma
  frequency: VERY_FREQUENT
  description: Medulloblastoma is the most common malignant brain tumor of childhood.
  evidence:
  - reference: PMID:41544627
    reference_title: "Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma."
    supports: SUPPORT
    snippet: "Medulloblastoma, the most common malignant brain tumor of childhood, exhibits"
    explanation: Abstract states medulloblastoma is the most common malignant brain tumor of childhood.

phenotypes:
- category: Neurological
  name: Headache
  frequency: VERY_FREQUENT
  description: >-
    Headache from increased intracranial pressure due to obstructive hydrocephalus.
    Often worse in morning.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
- category: Neurological
  name: Ataxia
  frequency: VERY_FREQUENT
  description: >-
    Cerebellar ataxia with appendicular (limb) involvement when tumor is lateral,
    or truncal instability with midline tumors.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
- category: Neurological
  name: Nausea and Vomiting
  frequency: VERY_FREQUENT
  description: >-
    Vomiting from increased intracranial pressure, often in the morning.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
- category: Neurological
  name: Macrocephaly
  frequency: FREQUENT
  description: >-
    Increased head circumference in infants due to hydrocephalus from CSF
    obstruction. May be the presenting sign in young infants.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
genetic:
- name: PTCH1
  association: Somatic/Germline Mutation
  notes: >-
    PTCH1 loss-of-function mutations occur in approximately 40-50% of SHH-activated
    medulloblastomas. Germline PTCH1 mutations cause Gorlin syndrome (nevoid basal
    cell carcinoma syndrome) with predisposition to medulloblastoma, basal cell
    carcinomas, and skeletal abnormalities.
  evidence:
  - reference: PMID:35489737
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."
    explanation: Directly supports PTCH1 as a recurrently mutated gene in SHH-activated medulloblastoma.
  - reference: PMID:26169613
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS"
    explanation: Provides clinical evidence that PTCH1 LOH defines a clinically meaningful SHH-MB subgroup with distinct vismodegib response.
- name: SMO
  association: Somatic Mutation
  notes: >-
    SMO activating mutations occur in approximately 10-15% of SHH-activated tumors,
    more common in adults. These mutations can confer resistance to SMO inhibitors
    and are targetable by different therapeutic approaches.
- name: SUFU
  association: Somatic/Germline Mutation
  notes: >-
    SUFU loss-of-function mutations occur in approximately 10% of SHH-activated
    medulloblastomas, particularly in infants. Germline SUFU mutations predispose
    to medulloblastoma. SUFU mutations cause pathway activation downstream of
    SMO, conferring resistance to SMO inhibitors.
  evidence:
  - reference: PMID:35489737
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."
    explanation: Directly supports SUFU as a recurrently mutated SHH pathway gene in SHH-activated medulloblastoma.
- name: GLI2
  association: Amplification
  notes: >-
    GLI2 amplification occurs in approximately 5-10% of SHH-activated tumors and
    is associated with worse prognosis. Causes pathway activation downstream of
    SMO, conferring resistance to SMO inhibitors.
  evidence:
  - reference: PMID:35489737
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SHH tumors contain mutations and alterations in GLI1, GLI2, SUFU, and PTCH1 genes, which constitutively activate the SHH pathway."
    explanation: Directly supports GLI2 as a recurrently altered SHH pathway gene in SHH-activated medulloblastoma.
- name: MYCN
  association: Amplification
  notes: >-
    MYCN amplification occurs in approximately 5-10% of SHH-activated tumors,
    often with TP53 mutation. Associated with worse prognosis and large
    cell/anaplastic features.
  evidence:
  - reference: PMID:35489737
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Originally, the presence of TP53 gene alterations and/or MYC amplifications was considered the most reliable prognostic factor."
    explanation: Supports the prognostic importance of MYC-family amplification in SHH medulloblastoma literature, but the abstract does not distinguish MYCN specifically.
- name: TP53
  association: Somatic/Germline Mutation
  notes: >-
    TP53 mutations occur in approximately 10-15% of SHH-activated medulloblastomas.
    May be germline (Li-Fraumeni syndrome) or somatic. Defines a high-risk
    subgroup with worse prognosis under WHO 2021 classification.
  evidence:
  - reference: PMID:35489737
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Originally, the presence of TP53 gene alterations and/or MYC amplifications was considered the most reliable prognostic factor."
    explanation: Directly supports TP53 mutation status as a key prognostic marker in SHH-activated medulloblastoma.
- name: TERT
  association: Promoter Mutation
  notes: >-
    TERT promoter mutations occur in approximately 20-30% of adult SHH-activated
    medulloblastomas and are associated with worse prognosis in adults.
  evidence:
  - reference: PMID:35489737
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recent molecular analyses have subdivided SHH MB into several subtypes with distinct characteristics such as age, TP53 mutation, MYC amplification, presence of metastases, TERT promoter alterations, PTEN loss, and other chromosomal alterations as well as SHH pathway-related gene mutations."
    explanation: Supports TERT promoter mutations as a recurrent molecular alteration that defines a SHH-activated medulloblastoma subtype.
treatments:
- name: Surgical Resection
  description: >-
    Maximal safe resection is first-line treatment. Lateral/hemispheric location
    often allows gross total resection. Extent of resection is prognostic.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:40199599
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gross total resection was achieved, and after a short recovery period, adjuvant craniospinal irradiation plus chemotherapy is started."
    explanation: Directly supports gross total surgical resection followed by adjuvant therapy as the standard care for medulloblastoma.
- name: Craniospinal Irradiation
  description: >-
    Craniospinal irradiation is standard for children >3 years due to risk of
    leptomeningeal spread. Radiation is typically avoided in infants (<3 years)
    due to severe neurocognitive effects.
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: MAXO:0000014
      label: radiation therapy
  evidence:
  - reference: PMID:40199599
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gross total resection was achieved, and after a short recovery period, adjuvant craniospinal irradiation plus chemotherapy is started."
    explanation: Directly supports adjuvant craniospinal irradiation as part of standard medulloblastoma management.
- name: Chemotherapy
  description: >-
    Multi-agent chemotherapy is standard. For infants, intensive chemotherapy
    regimens aim to delay or avoid radiation. Standard agents include cisplatin,
    vincristine, cyclophosphamide, and lomustine.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: MAXO:0000647
      label: chemotherapy
  evidence:
  - reference: PMID:40199599
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "adjuvant craniospinal irradiation plus chemotherapy is started."
    explanation: Directly supports adjuvant chemotherapy alongside radiation as part of standard medulloblastoma therapy.
- name: SHH Pathway Inhibitors (Vismodegib/Sonidegib)
  description: >-
    SMO inhibitors show activity in recurrent SHH-activated medulloblastoma with
    upstream pathway mutations (PTCH1). Resistance develops through SMO mutations
    or pathway activation downstream of SMO (GLI amplification, SUFU mutations).
    Growth plate toxicity limits use in children.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: vismodegib
      term:
        id: CHEBI:66903
        label: vismodegib
    - preferred_term: sonidegib
      term:
        id: CHEBI:90863
        label: sonidegib
  evidence:
  - reference: PMID:26169613
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH-MB."
    explanation: Phase II trial evidence directly supports vismodegib as targeted therapy for SHH-activated medulloblastoma.
  - reference: PMID:26169613
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses."
    explanation: Supports the mechanism of vismodegib resistance through downstream SMO pathway mutations (GLI/SUFU).
notes: >-
  SHH-activated medulloblastoma has a bimodal age distribution with peaks in
  infants (<3 years) and adults (>16 years). Infant SHH tumors often have
  desmoplastic/nodular or extensive nodularity histology and PTCH1/SUFU mutations
  with favorable prognosis. Adult SHH tumors more often have SMO mutations and
  TERT promoter mutations. TP53 mutation status is the major prognostic factor
  within this subgroup.
disease_term:
  preferred_term: medulloblastoma SHH activated
  term:
    id: MONDO:0850197
    label: medulloblastoma SHH activated

classifications:
  icdo_morphology:
    classification_value: Embryonal Neoplasm
  harrisons_chapter:
  - classification_value: cancer
  - classification_value: solid tumor
references:
- reference: DOI:10.1093/neuonc/noab031
  title: Integrated molecular analysis of adult sonic hedgehog (SHH)-activated medulloblastomas reveals two clinically relevant tumor subsets with VEGFA as potent prognostic indicator
  found_in:
  - Medulloblastoma_SHH_Activated-deep-research-falcon.md
  findings:
  - statement: Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology.
    supporting_text: Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology.
    evidence:
    - reference: DOI:10.1093/neuonc/noab031
      reference_title: Integrated molecular analysis of adult sonic hedgehog (SHH)-activated medulloblastomas reveals two clinically relevant tumor subsets with VEGFA as potent prognostic indicator
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology.
      explanation: Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.
- reference: DOI:10.1093/neuonc/noad027
  title: 'Risk prediction in early childhood sonic hedgehog medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than 2 subgroups'
  found_in:
  - Medulloblastoma_SHH_Activated-deep-research-falcon.md
  findings:
  - statement: 'Risk prediction in early childhood sonic hedgehog medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than 2 subgroups'
    supporting_text: The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse.
    evidence:
    - reference: DOI:10.1093/neuonc/noad027
      reference_title: 'Risk prediction in early childhood sonic hedgehog medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than 2 subgroups'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse.
      explanation: Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.
- reference: DOI:10.1093/noajnl/vdab097
  title: Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma
  found_in:
  - Medulloblastoma_SHH_Activated-deep-research-falcon.md
  findings:
  - statement: Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth.
    supporting_text: Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth.
    evidence:
    - reference: DOI:10.1093/noajnl/vdab097
      reference_title: Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth.
      explanation: Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.
- reference: DOI:10.1093/noajnl/vdac026
  title: Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma
  found_in:
  - Medulloblastoma_SHH_Activated-deep-research-falcon.md
  findings:
  - statement: Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients.
    supporting_text: Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients.
    evidence:
    - reference: DOI:10.1093/noajnl/vdac026
      reference_title: Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients.
      explanation: Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.
- reference: DOI:10.3390/brainsci15080896
  title: 'Advancing Medulloblastoma Therapy in Pediatrics: Integrative Molecular Classification and Emerging Treatments'
  found_in:
  - Medulloblastoma_SHH_Activated-deep-research-falcon.md
  findings:
  - statement: 'Medulloblastoma (MB), the most common malignant pediatric brain tumor, has undergone reclassification from a histologically defined disease to a genetically stratified spectrum of distinct subgroups: WNT, SHH, Group 3, and Group 4.'
    supporting_text: 'Medulloblastoma (MB), the most common malignant pediatric brain tumor, has undergone reclassification from a histologically defined disease to a genetically stratified spectrum of distinct subgroups: WNT, SHH, Group 3, and Group 4.'
    evidence:
    - reference: DOI:10.3390/brainsci15080896
      reference_title: 'Advancing Medulloblastoma Therapy in Pediatrics: Integrative Molecular Classification and Emerging Treatments'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Medulloblastoma (MB), the most common malignant pediatric brain tumor, has undergone reclassification from a histologically defined disease to a genetically stratified spectrum of distinct subgroups: WNT, SHH, Group 3, and Group 4.'
      explanation: Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.
- reference: DOI:10.3390/cancers15153889
  title: 'The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies'
  found_in:
  - Medulloblastoma_SHH_Activated-deep-research-falcon.md
  findings:
  - statement: Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population.
    supporting_text: Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population.
    evidence:
    - reference: DOI:10.3390/cancers15153889
      reference_title: 'The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population.
      explanation: Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.
- reference: DOI:10.3390/cimb48030297
  title: 'Medulloblastoma in Adolescents and Young Adults: Molecular Subgroups, Prognostic Biomarkers, and Age-Specific Therapeutic Challenges'
  found_in:
  - Medulloblastoma_SHH_Activated-deep-research-falcon.md
  findings:
  - statement: Medulloblastoma is the most common malignant brain tumor in children, but it presents distinct challenges when occurring in adolescents and young adults (AYAs, aged 15–39 years).
    supporting_text: Medulloblastoma is the most common malignant brain tumor in children, but it presents distinct challenges when occurring in adolescents and young adults (AYAs, aged 15–39 years).
    evidence:
    - reference: DOI:10.3390/cimb48030297
      reference_title: 'Medulloblastoma in Adolescents and Young Adults: Molecular Subgroups, Prognostic Biomarkers, and Age-Specific Therapeutic Challenges'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Medulloblastoma is the most common malignant brain tumor in children, but it presents distinct challenges when occurring in adolescents and young adults (AYAs, aged 15–39 years).
      explanation: Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.
- reference: DOI:10.3390/jmp6020011
  title: The Current Landscape of Molecular Pathology for the Diagnosis and Treatment of Pediatric Medulloblastoma
  found_in:
  - Medulloblastoma_SHH_Activated-deep-research-falcon.md
  findings:
  - statement: Medulloblastoma (MB) is a malignant brain tumor that requires intense multimodal treatment.
    supporting_text: Medulloblastoma (MB) is a malignant brain tumor that requires intense multimodal treatment.
    evidence:
    - reference: DOI:10.3390/jmp6020011
      reference_title: The Current Landscape of Molecular Pathology for the Diagnosis and Treatment of Pediatric Medulloblastoma
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Medulloblastoma (MB) is a malignant brain tumor that requires intense multimodal treatment.
      explanation: Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.

📚

References & Deep Research

References

8

DOI:10.1093/neuonc/noab031

Integrated molecular analysis of adult sonic hedgehog (SHH)-activated medulloblastomas reveals two clinically relevant tumor subsets with VEGFA as potent prognostic indicator

1 finding

Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology.

"Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology."

Show evidence (1 reference)

DOI:10.1093/neuonc/noab031 SUPPORT Other

"Up to now, adult medulloblastoma (MB) patients are treated according to the protocols elaborated for pediatric MB although these tumors are different in terms of clinical outcomes and biology."

Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.

DOI:10.1093/neuonc/noad027

Risk prediction in early childhood sonic hedgehog medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than 2 subgroups

1 finding

Risk prediction in early childhood sonic hedgehog medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than 2 subgroups

"The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse."

Show evidence (1 reference)

DOI:10.1093/neuonc/noad027 SUPPORT Human Clinical

"The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse."

Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.

DOI:10.1093/noajnl/vdab097

Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma

1 finding

Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth.

"Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth."

Show evidence (1 reference)

DOI:10.1093/noajnl/vdab097 SUPPORT Human Clinical

"Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth."

Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.

DOI:10.1093/noajnl/vdac026

Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma

1 finding

Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients.

"Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients."

Show evidence (1 reference)

DOI:10.1093/noajnl/vdac026 SUPPORT Human Clinical

"Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients."

Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.

DOI:10.3390/brainsci15080896

Advancing Medulloblastoma Therapy in Pediatrics: Integrative Molecular Classification and Emerging Treatments

1 finding

Medulloblastoma (MB), the most common malignant pediatric brain tumor, has undergone reclassification from a histologically defined disease to a genetically stratified spectrum of distinct subgroups: WNT, SHH, Group 3, and Group 4.

"Medulloblastoma (MB), the most common malignant pediatric brain tumor, has undergone reclassification from a histologically defined disease to a genetically stratified spectrum of distinct subgroups: WNT, SHH, Group 3, and Group 4."

Show evidence (1 reference)

DOI:10.3390/brainsci15080896 SUPPORT Human Clinical

"Medulloblastoma (MB), the most common malignant pediatric brain tumor, has undergone reclassification from a histologically defined disease to a genetically stratified spectrum of distinct subgroups: WNT, SHH, Group 3, and Group 4."

Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.

DOI:10.3390/cancers15153889

The Neurodevelopmental and Molecular Landscape of Medulloblastoma Subgroups: Current Targets and the Potential for Combined Therapies

1 finding

Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population.

"Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population."

Show evidence (1 reference)

DOI:10.3390/cancers15153889 SUPPORT Human Clinical

"Medulloblastoma is the most common malignant pediatric brain tumor and is associated with significant morbidity and mortality in the pediatric population."

Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.

DOI:10.3390/cimb48030297

Medulloblastoma in Adolescents and Young Adults: Molecular Subgroups, Prognostic Biomarkers, and Age-Specific Therapeutic Challenges

1 finding

Medulloblastoma is the most common malignant brain tumor in children, but it presents distinct challenges when occurring in adolescents and young adults (AYAs, aged 15–39 years).

"Medulloblastoma is the most common malignant brain tumor in children, but it presents distinct challenges when occurring in adolescents and young adults (AYAs, aged 15–39 years)."

Show evidence (1 reference)

DOI:10.3390/cimb48030297 SUPPORT Human Clinical

"Medulloblastoma is the most common malignant brain tumor in children, but it presents distinct challenges when occurring in adolescents and young adults (AYAs, aged 15–39 years)."

Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.

DOI:10.3390/jmp6020011

The Current Landscape of Molecular Pathology for the Diagnosis and Treatment of Pediatric Medulloblastoma

1 finding

Medulloblastoma (MB) is a malignant brain tumor that requires intense multimodal treatment.

"Medulloblastoma (MB) is a malignant brain tumor that requires intense multimodal treatment."

Show evidence (1 reference)

DOI:10.3390/jmp6020011 SUPPORT Human Clinical

"Medulloblastoma (MB) is a malignant brain tumor that requires intense multimodal treatment."

Deep research cited this publication as relevant literature for Medulloblastoma SHH Activated.

Deep Research

1

Falcon ▸

1. Disease Information

Edison Scientific Literature 31 citations 2026-05-09T12:11:05.283581

1. Disease Information

1.1 Overview and current definition

SHH-activated medulloblastoma is a molecularly defined subgroup of medulloblastoma characterized by activation of Sonic Hedgehog signaling and recognized in the WHO 2021 (WHO CNS5) integrated classification framework. WHO CNS5 further separates SHH-activated medulloblastoma into TP53-wildtype and TP53-mutant types, reflecting major prognostic differences. (koch2025thecurrentlandscape pages 2-4)

1.2 Common synonyms / alternative names

“SHH medulloblastoma”
“Sonic Hedgehog medulloblastoma”
“Hedgehog pathway–activated medulloblastoma”
“SHH-activated medulloblastoma, TP53-wildtype”
“SHH-activated medulloblastoma, TP53-mutant” (koch2025thecurrentlandscape pages 2-4)

1.3 Evidence source types

The evidence supporting disease definition and subclassification here is derived from aggregated disease-level resources (reviews and multi-institutional cohorts) and clinical trial registries (ClinicalTrials.gov), not EHR data. (koch2025thecurrentlandscape pages 2-4, NCT01708174 chunk 1, NCT00939484 chunk 1)

2. Etiology

2.1 Primary causal/mechanistic factors

SHH-activated medulloblastoma is driven by genomic events that activate Hedgehog signaling at the level of pathway repressors and transducers (e.g., PTCH1, SMO, SUFU) and downstream effectors (e.g., GLI2 amplification), often in age-dependent patterns. (koch2025thecurrentlandscape pages 2-4, kim2025advancingmedulloblastomatherapy pages 4-6)

2.2 Risk factors

Genetic risk factors

Germline predisposition is enriched in SHH tumors compared with other medulloblastoma groups and includes:
Gorlin syndrome (classically PTCH1; also SUFU) (koch2025thecurrentlandscape pages 2-4, kim2025advancingmedulloblastomatherapy pages 4-6)
Li–Fraumeni syndrome (TP53) (koch2025thecurrentlandscape pages 2-4)

Environmental risk factors

No specific, well-supported environmental exposures were identified in the retrieved sources for SHH-activated medulloblastoma.

2.3 Protective factors

Protective factors were not identified in the retrieved evidence.

2.4 Gene–environment interactions

No SHH-specific gene–environment interaction evidence was identified in the retrieved corpus.

3. Phenotypes

3.1 Clinical presentation (typical)

SHH-activated medulloblastoma commonly presents with symptoms and signs attributable to a posterior fossa mass and/or hydrocephalus. In adolescents/young adults (AYAs), reported presenting symptoms include nausea/vomiting, headache, and ataxia, with potential diagnostic delay. (ruggiero2026medulloblastomainadolescents pages 2-4)

3.2 Age distribution and anatomic tendencies

SHH tumors show a bimodal age distribution enriched in infants (<3 years) and adults. (ruggiero2026medulloblastomainadolescents pages 2-4, koch2025thecurrentlandscape pages 2-4)
In adults, SHH molecular signature is common among medulloblastomas (reported ~70% in an adult series context statement). (korshunov2021integratedmolecularanalysis pages 1-2)

3.3 HPO term suggestions (non-exhaustive)

Common clinical manifestations to map: - Headache — HP:0002315 - Nausea — HP:0002018 - Vomiting — HP:0002013 - Ataxia — HP:0001251 - Hydrocephalus — HP:0000238 - Increased intracranial pressure — HP:0002516

(Ontology suggestions are provided for KB normalization; frequencies were not consistently extractable from the retrieved SHH-specific sources.)

4. Genetic / Molecular Information

4.1 Key causal/driver genes and alterations

Common SHH-pathway drivers and subgroup modifiers include: - PTCH1 (loss-of-function; germline or somatic), SMO (activating), SUFU (loss-of-function), GLI2/GLI1 amplification, MYCN amplification, TP53 alteration (esp. high-risk childhood), and TERT promoter mutation in adult-associated SHH subtypes. (koch2025thecurrentlandscape pages 2-4, kim2025advancingmedulloblastomatherapy pages 4-6, ruggiero2026medulloblastomainadolescents pages 2-4)

A review table summarizing major SHH alterations lists TP53, TERT, PTCH1 and also GLI2, SMO, SUFU as commonly reported alterations in SHH medulloblastoma. (slika2023theneurodevelopmentaland pages 1-2)

4.2 DNA methylation / transcriptomic subclasses

Two widely used frameworks appear in the retrieved evidence: 1) SHH-α / SHH-β / SHH-γ / SHH-δ (Cavalli-style) subclasses with age associations (infant vs child vs adult) and distinct genomics including TERT promoter enrichment in adult-associated classes. (korshunov2021integratedmolecularanalysis pages 2-3, ruggiero2026medulloblastomainadolescents pages 2-4, kim2025advancingmedulloblastomatherapy pages 4-6) 2) WHO 2021 early-childhood SHH methylation classes: SHH-1, SHH-2, SHH-3, with evidence that SHH-2 can be further divided into SHH-2a and SHH-2b with distinct relapse risk in radiation-avoiding cohorts. (tonn2023riskpredictionin pages 1-2)

4.3 Somatic vs germline

Both germline and somatic alterations contribute: - Germline: PTCH/SUFU (Gorlin), TP53 (Li–Fraumeni). (koch2025thecurrentlandscape pages 2-4, kim2025advancingmedulloblastomatherapy pages 4-6) - Somatic: PTCH1/SMO/SUFU mutations and amplifications (e.g., GLI2, MYCN). (kim2025advancingmedulloblastomatherapy pages 4-6, ruggiero2026medulloblastomainadolescents pages 2-4)

4.4 Epigenetics

Genome-wide DNA methylation signatures are clinically leveraged for medulloblastoma subgrouping and SHH subclassification (e.g., Heidelberg classifier use in cohorts and trials). (tonn2023riskpredictionin pages 3-5, NCT01708174 chunk 1)

5. Mechanism / Pathophysiology

5.1 Core pathway mechanism (causal chain)

A simplified causal chain consistent with retrieved clinical/translational sources: 1) Genomic activation of the SHH pathway via loss of negative regulation (PTCH1/SUFU) or activation of transduction (SMO) (kim2025advancingmedulloblastomatherapy pages 4-6, ruggiero2026medulloblastomainadolescents pages 2-4) 2) GLI transcription factor program activation (downstream of SMO/SUFU axis) promoting proliferation/survival programs in cerebellar developmental lineages (kim2025advancingmedulloblastomatherapy pages 4-6) 3) Emergence of SHH medulloblastoma with subgroup-specific patterns of chromosomal alterations and oncogene amplification (e.g., MYCN/GLI2) that influence aggressiveness and treatment response (kim2025advancingmedulloblastomatherapy pages 4-6, ruggiero2026medulloblastomainadolescents pages 2-4)

5.2 Cell(s) of origin / lineage context

SHH tumors are described as arising from cerebellar granule neuron precursor lineage / granule lineage precursors (broadly consistent across review and AYA-focused summaries). (ruggiero2026medulloblastomainadolescents pages 2-4, charton2024modellingtheeffects pages 13-17)

5.3 Suggested GO biological process terms

Hedgehog signaling pathway — GO:0007224
Regulation of cell proliferation — GO:0042127
DNA damage response (relevant to TP53-mutant biology) — GO:0006974

5.4 Suggested Cell Ontology (CL) terms

Cerebellar granule cell precursor — (candidate CL term; exact CL ID should be confirmed in CL/UBERON crosswalk)

6. Inheritance and Population

6.1 Inheritance patterns (predisposition)

Inheritance applies primarily to tumor predisposition syndromes: - Autosomal dominant predisposition syndromes such as Gorlin (PTCH1/SUFU) and Li–Fraumeni (TP53). (koch2025thecurrentlandscape pages 2-4)

6.2 Epidemiology and subgroup proportions

SHH-activated medulloblastoma accounts for ~25–30% of medulloblastomas overall in multiple summaries. (koch2025thecurrentlandscape pages 2-4, slika2023theneurodevelopmentaland pages 1-2)
In an adult SHH cohort study context statement, SHH signature is more frequent in adult medulloblastoma (~70%) than pediatric (~30%). (korshunov2021integratedmolecularanalysis pages 1-2)

Note: Population-based incidence rates specific to SHH-activated medulloblastoma (e.g., CBTRUS molecular subtype incidence) were not extractable from the retrieved CBTRUS text segments during this run.

7. Diagnostics

7.1 Integrated diagnosis approach

Modern diagnostic practice is layered/integrated: histopathology plus molecular subgroup assignment, increasingly via genome-wide methylation profiling. A molecular pathology review states WHO CNS5 recognizes four major medulloblastoma molecular subgroups by DNA methylation profiling and notes defining the molecular subgroup by methylation profiling as standard-of-care framing in contemporary practice. (koch2025thecurrentlandscape pages 2-4)

7.2 DNA methylation profiling (practical implementation)

A major early-childhood cohort used Illumina 450K/EPIC methylation arrays and referenced a Heidelberg Brain Tumor Classifier version (v12.5) in subclass assignment and risk modeling; this illustrates real-world feasibility of methylation-driven SHH subclassification in cooperative cohorts. (tonn2023riskpredictionin pages 3-5)

7.3 Sequencing

Targeted sequencing and/or exome sequencing is used to identify actionable/pathway-defining variants (PTCH1/SMO/SUFU; TP53; amplifications) and to interpret resistance (e.g., acquired SMO mutations after SMO inhibitor exposure). (pereira2021clinicalandmolecular pages 2-3)

7.4 Differential diagnosis

Differential diagnosis in posterior fossa pediatric tumors includes other medulloblastoma molecular groups (WNT, Group 3, Group 4) and other embryonal tumors; subgrouping by methylation profiling is a central discriminator in current practice. (koch2025thecurrentlandscape pages 2-4)

8. Outcome / Prognosis

8.1 Prognostic stratifiers

TP53 mutation status in SHH medulloblastoma is repeatedly highlighted as a major adverse prognostic factor, with approximate 5-year survival differences on the order of ~80% (TP53-wildtype) vs ~40% (TP53-mutant) in one molecular pathology review summary. (koch2025thecurrentlandscape pages 2-4)

8.2 Early-childhood SHH prognosis under radiation-avoiding therapy (key statistics)

A large cohort of 144 children <5 years with SHH desmoplastic/nodular MB or MBEN treated with radiation-sparing chemotherapy reported (overall cohort): - 5-year PFS 78% and 5-year OS 93% (tonn2023riskpredictionin pages 3-5) - Histology/age effects: MBEN 5-year PFS 93% vs DMB 71%; age >3 years associated with 5-year PFS 47% vs 84–85% for younger age bands. (tonn2023riskpredictionin pages 1-2)

Subgroup-level risk differences were identified with methylation subclassing: - 5-year PFS in the primary cohort: SHH-2a 95%, SHH-1 83%, SHH-2b 58%. (tonn2023riskpredictionin pages 1-2)

A key figure (hierarchical clustering and Kaplan–Meier) additionally summarizes combined-cohort differences (5-year PFS SHH-2a 87%, SHH-1 68%, SHH-2b 48%). (tonn2023riskpredictionin media 3b1240bb)

8.3 Adult SHH molecular subsets and prognosis

In a study of 96 adult SHH medulloblastomas, two epigenetic subsets were defined with markedly different outcomes: - Favorable subset aSHH-MBI: 5-year PFS 80%, OS 92% - Unfavorable subset aSHH-MBII: 5-year PFS 24%, OS 45%

Direct abstract quote: “We defined two aSHH-MB numerically comparable epigenetic subsets…” with the unfavorable subset showing “5-year PFS = 24% and OS = 45%”. (korshunov2021integratedmolecularanalysis pages 1-2)

9. Treatment

9.1 Current standard backbone (real-world implementation)

Multimodal therapy is generally based on maximal safe resection plus risk-adapted radiotherapy and multiagent chemotherapy; however, in infants/very young children, craniospinal irradiation is often delayed/avoided, and SHH infant tumors may be cured with chemotherapy-only approaches in selected contexts. (tonn2023riskpredictionin pages 1-2, kim2025advancingmedulloblastomatherapy pages 10-12)

9.2 Targeted therapy: SMO inhibitors (vismodegib, sonidegib)

Clinical activity and predictive biomarkers

A retrospective series of young patients treated with SMO inhibitors for recurrent SHH medulloblastoma reported: - “All patients with a somatic PTCH1 mutation responded to SMOi (6/8), including 2 prolonged complete responses.” (pereira2021clinicalandmolecular pages 1-2) - “One patient was free of disease 8.2 years after treatment.” (pereira2021clinicalandmolecular pages 1-2) - Overall 6/8 (75%) objective responses (4 PR, 2 CR) in detailed excerpted reporting. (pereira2021clinicalandmolecular pages 2-3)

Toxicities (key safety considerations)

Severe or clinically limiting toxicities included “myalgia and growth plate fusion with metaphyseal sclerosis” in the SMO inhibitor series; the authors highlight developmental toxicity as a key limitation for pediatric use. (pereira2021clinicalandmolecular pages 1-2)

Resistance mechanisms

Resistance can emerge via acquired SMO mutations: - Clinical relapse biopsies after SMO inhibitor treatment showed “SMO resistance mutations”. (pereira2021clinicalandmolecular pages 1-2) - This is supported by preclinical modeling where sonidegib-resistant PDX lines frequently developed SMO missense mutations (mechanistic corroboration). (pereira2021clinicalandmolecular pages 1-2)

9.3 Selected ClinicalTrials.gov implementations (NCTs)

Clinical trial registry records show how SHH activation is operationalized and which endpoints are used.

Vismodegib in recurrent/refractory medulloblastoma (adults) - NCT00939484 (Phase II, completed; N=31). Stratified by PTCH/SHH pathway activation; primary endpoint objective response sustained ≥8 weeks. (NCT00939484 chunk 1) - URL: https://clinicaltrials.gov/study/NCT00939484 (start: 2009-06; completion: 2015-08 per record excerpt). (NCT00939484 chunk 1)

Vismodegib + temozolomide vs temozolomide alone (adults, SHH activation required) - NCT01601184 (Phase I/II, randomized, open-label; terminated early). Required “activation of the Sonic Hedgehog Pathway” by IHC; Phase II primary endpoint: “6-month progression-free rate.” (NCT01601184 chunk 1) - URL: https://clinicaltrials.gov/study/NCT01601184 (first posted 2012). (NCT01601184 chunk 1)

Sonidegib (LDE225) in pediatric/adult recurrent tumors with Hh dependence - NCT01125800 (Phase I/II, single-group; N=76). Pediatric dose escalation; ORR assessed by Hh signaling status (Hh-positive vs Hh-negative). (NCT01125800 chunk 1) - URL: https://clinicaltrials.gov/study/NCT01125800 (first posted 2011). (NCT01125800 chunk 1)

Sonidegib in Hh-pathway activated relapsed medulloblastoma - NCT01708174 (Phase II; completed; N=22). Eligibility required “Hh-pathway activation by the 5-gene Hh signature assay”; primary endpoint ORR by independent review. (NCT01708174 chunk 1) - URL: https://clinicaltrials.gov/study/NCT01708174 (start date 2013-05-06 per record excerpt). (NCT01708174 chunk 1)

9.4 MAXO (Medical Action Ontology) term suggestions

Surgical tumor resection — MAXO (surgical excision; confirm exact MAXO ID)
Craniospinal irradiation — MAXO (radiotherapy)
Combination chemotherapy — MAXO (chemotherapy)
Smoothened inhibitor therapy (vismodegib/sonidegib) — MAXO (targeted small-molecule therapy)
High-dose chemotherapy with autologous stem cell rescue — MAXO (hematopoietic stem cell transplantation adjunct)

10. Prevention

10.1 Primary prevention

No validated primary prevention measures were identified.

10.2 Secondary/tertiary prevention: predisposition recognition and therapy modification

Given non-trivial germline predisposition in SHH tumors, an actionable prevention-like strategy is early identification of tumor predisposition syndromes and therapy adaptation. For example, reviews note radiotherapy should be used cautiously in germline predisposition settings (e.g., Gorlin/Li–Fraumeni) due to risk of secondary neoplasms. (koch2025thecurrentlandscape pages 2-4)

11. Other Species / Natural Disease

No naturally occurring non-human SHH-medulloblastoma evidence was retrieved in this run.

12. Model Organisms / Experimental Models

Multiple translational approaches underpin SHH biology and drug discovery, including: - Patient-derived xenograft (PDX) models for studying SMO inhibitor resistance (generated sonidegib-resistant lines). (pereira2021clinicalandmolecular pages 1-2) - Early developmental-lineage modeling to interpret differentiation blockade in SHH medulloblastoma (reviewed at high level in modeling-focused sources). (charton2024modellingtheeffects pages 13-17)

Suggested model annotations (non-exhaustive): - Mouse SHH pathway models (Ptch1/Sufu/Sm o alterations) - Orthotopic xenografts (PDX)

Recent developments and “latest research” highlights (prioritizing 2023–2024)

1) Risk prediction refinement within early-childhood SHH under radiotherapy-avoiding regimens: SHH-2 subdivides into SHH-2a vs SHH-2b with markedly different relapse risk (5-year PFS differences). (tonn2023riskpredictionin pages 1-2, tonn2023riskpredictionin media 3b1240bb) 2) Growing clinical operationalization of methylation classes in cooperative cohorts via Heidelberg classifier versions (e.g., v12.5). (tonn2023riskpredictionin pages 3-5) 3) Clinical translation of pathway-targeted therapy remains focused on SMO inhibitors with known pediatric skeletal toxicity and resistance mutations, emphasizing the need for combination strategies and biomarker-driven selection (e.g., PTCH1-mutated responders). (pereira2021clinicalandmolecular pages 1-2, NCT01601184 chunk 1)

Evidence summary table

The following table consolidates the key classification, molecular features, outcomes, and targeted-therapy evidence retrieved in this run.

Topic	Key facts (with numbers)	Evidence type (review/clinical cohort/trial)	Primary source (short citation with year)	URL	Pub date	Citation ID
Definition / WHO CNS5 types	SHH-activated medulloblastoma is one of 4 principal medulloblastoma molecular groups and WHO CNS5 separates it into SHH-activated, TP53-wildtype and SHH-activated, TP53-mutant entities; SHH tumors comprise about 25–30% of medulloblastomas overall (koch2025thecurrentlandscape pages 2-4, slika2023theneurodevelopmentaland pages 1-2)	Review / classification summary	Koch et al., 2025	https://doi.org/10.3390/jmp6020011	2025-06	(koch2025thecurrentlandscape pages 2-4)
Age distribution / localization	SHH tumors show a bimodal age distribution, enriched in infants (<3 years) and adults/AYA, and are often lateral/cerebellar hemisphere tumors; in adults SHH accounts for about ~65–70% of medulloblastoma, versus ~30% in pediatric cohorts (korshunov2021integratedmolecularanalysis pages 1-2, ruggiero2026medulloblastomainadolescents pages 2-4, kim2025advancingmedulloblastomatherapy pages 4-6)	Review + molecular cohort	Korshunov et al., 2021	https://doi.org/10.1093/neuonc/noab031	2021-02	(korshunov2021integratedmolecularanalysis pages 1-2)
Core driver pathway lesions	Canonical SHH-pathway alterations include PTCH1, SMO, SUFU mutations and downstream GLI2/GLI1 amplification; pediatric high-risk SHH often also shows MYCN amplification and TP53 alteration; adult SHH is enriched for PTCH1/SMO mutations (koch2025thecurrentlandscape pages 2-4, kim2025advancingmedulloblastomatherapy pages 4-6)	Review	Kim et al., 2025	https://doi.org/10.3390/brainsci15080896	2025-08	(kim2025advancingmedulloblastomatherapy pages 4-6)
Predisposition syndromes	Major germline predisposition syndromes are Gorlin syndrome (PTCH1 or SUFU) and Li-Fraumeni syndrome (TP53); SHH has the highest rate of tumor-predisposition among medulloblastoma groups, and radiation requires caution in Gorlin/LFS because of secondary neoplasm risk (koch2025thecurrentlandscape pages 2-4, kim2025advancingmedulloblastomatherapy pages 4-6)	Review / hereditary risk summary	Koch et al., 2025	https://doi.org/10.3390/jmp6020011	2025-06	(koch2025thecurrentlandscape pages 2-4)
Methylation subtypes (broad)	SHH can be subclassified by methylation/transcriptomics into SHH-α, SHH-β, SHH-γ, SHH-δ. SHH-α: older children, enriched for TP53, MYCN, GLI2; poorer prognosis. SHH-β/γ: infant-predominant. SHH-δ: adult-predominant and enriched for TERT promoter mutation (korshunov2021integratedmolecularanalysis pages 2-3, ruggiero2026medulloblastomainadolescents pages 2-4, kim2025advancingmedulloblastomatherapy pages 4-6)	Molecular cohort + review	Korshunov et al., 2021	https://doi.org/10.1093/neuonc/noab031	2021-02	(korshunov2021integratedmolecularanalysis pages 2-3)
Early-childhood methylation classes	In children <5 years treated with radiation-sparing chemotherapy, tumors were reclassified into SHH-1 (n=39), SHH-2 (n=38), SHH-3 (n=1); hierarchical clustering further split SHH-2 into SHH-2a (n=19) and SHH-2b (n=19) (tonn2023riskpredictionin pages 1-2, tonn2023riskpredictionin pages 2-3)	Clinical cohort	Tonn et al., 2023	https://doi.org/10.1093/neuonc/noad027	2023-01	(tonn2023riskpredictionin pages 1-2)
Early-childhood subgroup biology	SHH-2a was enriched for MBEN histology and correlated with SMO mutations; SHH-2b occurred in older DMB patients, more often lateral tumors, and showed more 9q loss with higher relapse risk (tonn2023riskpredictionin pages 1-2, tonn2023riskpredictionin media 3b1240bb)	Clinical cohort + image-supported figure summary	Tonn et al., 2023	https://doi.org/10.1093/neuonc/noad027	2023-01	(tonn2023riskpredictionin pages 1-2)
Early-childhood chemo-only outcomes	In 144 early-childhood SHH DMB/MBEN patients managed with radiation-avoiding therapy, overall 5-year PFS 78% and 5-year OS 93%; MBEN had 5-year PFS 93% vs 71% for DMB; age >3 years had worse 5-year PFS 47% vs 85% (<1 y) and 84% (1–3 y) (tonn2023riskpredictionin pages 1-2, tonn2023riskpredictionin pages 3-5)	Clinical cohort	Tonn et al., 2023	https://doi.org/10.1093/neuonc/noad027	2023-01	(tonn2023riskpredictionin pages 3-5)
Early-childhood subgroup prognosis	In the primary early-childhood cohort, 5-year PFS was 95% for SHH-2a, 83% for SHH-1, and 58% for SHH-2b; in the combined-cohort figure, corresponding 5-year PFS was 87%, 68%, and 48% respectively (tonn2023riskpredictionin pages 1-2, tonn2023riskpredictionin media 3b1240bb)	Clinical cohort	Tonn et al., 2023	https://doi.org/10.1093/neuonc/noad027	2023-01	(tonn2023riskpredictionin pages 1-2, tonn2023riskpredictionin media 3b1240bb)
TP53 effect on prognosis	TP53 status is a major prognostic discriminator: approximately 5-year survival ~80% for TP53-wildtype SHH versus about ~40% for TP53-mutant SHH; in AYA-focused summaries, 5-year OS ~70–80% for TP53-wildtype vs ~40–50% for TP53-mutant (koch2025thecurrentlandscape pages 2-4, ruggiero2026medulloblastomainadolescents pages 2-4)	Review	Koch et al., 2025	https://doi.org/10.3390/jmp6020011	2025-06	(koch2025thecurrentlandscape pages 2-4)
Adult SHH molecular subsets	In 96 adult SHH tumors, two clinically relevant epigenetic subsets were identified: aSHH-MBI with PTCH1/SMO mutations and favorable outcome (5-year PFS 80%, OS 92%), versus aSHH-MBII with GLI2 amplification (8%), 10q loss (22%), angiogenesis/VEGFA program, and poor outcome (5-year PFS 24%, OS 45%) (korshunov2021integratedmolecularanalysis pages 1-2)	Molecular clinical cohort	Korshunov et al., 2021	https://doi.org/10.1093/neuonc/noab031	2021-02	(korshunov2021integratedmolecularanalysis pages 1-2)
Diagnostic standard	Modern diagnosis is integrated histology + molecular testing; genome-wide DNA methylation profiling is described as standard of care / cornerstone for subgroup assignment, including SHH, and Heidelberg methylation classifier versions (e.g., v12.5/v12.8) are used in clinical/research workflows (koch2025thecurrentlandscape pages 2-4, tonn2023riskpredictionin pages 3-5)	Review + clinical cohort methods	Koch et al., 2025	https://doi.org/10.3390/jmp6020011	2025-06	(koch2025thecurrentlandscape pages 2-4)
SMO inhibitor activity	In a recurrent SHH series of 8 patients treated with vismodegib or sonidegib, there were 6/8 (75%) objective responses (4 PR, 2 CR); all evaluable tumors with somatic PTCH1 mutation responded and one patient remained disease-free 8.2 years after treatment (pereira2021clinicalandmolecular pages 1-2, pereira2021clinicalandmolecular pages 2-3)	Clinical series	Pereira et al., 2021	https://doi.org/10.1093/noajnl/vdab097	2021-07	(pereira2021clinicalandmolecular pages 1-2, pereira2021clinicalandmolecular pages 2-3)
SMO inhibitor treatment details	In the same series, vismodegib was used in 3 patients and sonidegib in 5; median age at start was 11.1 years (range 3.3–25.5) and median treatment duration was 7 months (range 1.2–9.4 months) (pereira2021clinicalandmolecular pages 2-3)	Clinical series	Pereira et al., 2021	https://doi.org/10.1093/noajnl/vdab097	2021-07	(pereira2021clinicalandmolecular pages 2-3)
SMO inhibitor toxicities	Key toxicities include myalgia and especially growth plate fusion / metaphyseal sclerosis; this skeletal toxicity is a major limitation in children and has led to preference for use in skeletally mature patients or carefully selected salvage settings (pereira2021clinicalandmolecular pages 1-2, kim2025advancingmedulloblastomatherapy pages 12-14)	Clinical series + review	Pereira et al., 2021	https://doi.org/10.1093/noajnl/vdab097	2021-07	(pereira2021clinicalandmolecular pages 1-2)
SMO inhibitor resistance	Resistance commonly arises through acquired SMO missense mutations; in a resistant PDX model, 8/9 sonidegib-resistant lines developed SMO missense mutations and 1/9 acquired an inactivating MEGF8 mutation downstream of SMO. Relapse biopsies from treated patients also showed SMO resistance mutations (pereira2021clinicalandmolecular pages 1-2, pereira2021clinicalandmolecular pages 2-3)	Preclinical model + clinical series	Krausert et al., 2022	https://doi.org/10.1093/noajnl/vdac026	2022-03	(pereira2021clinicalandmolecular pages 1-2, pereira2021clinicalandmolecular pages 2-3)
Practical therapeutic implication	SHH inhibitors are most compelling in PTCH1-mutated recurrent SHH medulloblastoma; combination strategies with temozolomide or local therapy (surgery/radiotherapy) were associated with prolonged disease control in selected patients (pereira2021clinicalandmolecular pages 1-2)	Clinical series	Pereira et al., 2021	https://doi.org/10.1093/noajnl/vdab097	2021-07	(pereira2021clinicalandmolecular pages 1-2)

Table: This table condenses the highest-yield classification, molecular, prognostic, and treatment evidence for SHH-activated medulloblastoma. It is designed to support a structured disease report with recent reviews plus key primary cohort and therapy data.

Notes on gaps / limitations of this run

Ontology identifiers (MONDO/OMIM/Orphanet/ICD/MeSH) and population incidence rates from registry reports were not reliably extractable from the retrieved texts using the current tool outputs; filling these fields will require targeted retrieval from dedicated ontology resources or explicit registry sections not captured here.
Several core statements are supported by reviews rather than primary genomic discovery papers due to corpus constraints; nevertheless, key numerical outcomes and trial design details were sourced from primary cohorts and ClinicalTrials.gov where possible. (tonn2023riskpredictionin pages 1-2, NCT00939484 chunk 1, NCT01708174 chunk 1)

References

(koch2025thecurrentlandscape pages 2-4): Alayna Koch, Ashley Childress, Emma Vallee, Alyssa Steller, and Scott Raskin. The current landscape of molecular pathology for the diagnosis and treatment of pediatric medulloblastoma. Journal of Molecular Pathology, 6:11, Jun 2025. URL: https://doi.org/10.3390/jmp6020011, doi:10.3390/jmp6020011. This article has 3 citations.
(NCT01708174 chunk 1): A Phase II Study of Oral LDE225 in Patients With Hedge-Hog (Hh)-Pathway Activated Relapsed Medulloblastoma (MB). Novartis Pharmaceuticals. 2013. ClinicalTrials.gov Identifier: NCT01708174
(NCT00939484 chunk 1): Vismodegib in Treating Patients With Recurrent or Refractory Medulloblastoma. National Cancer Institute (NCI). 2009. ClinicalTrials.gov Identifier: NCT00939484
(kim2025advancingmedulloblastomatherapy pages 4-6): David T. Kim, Michaela Uloho-Okundaye, Stephen C. Frederico, Santosh Guru, Min J. Kim, and Steven D. Chang. Advancing medulloblastoma therapy in pediatrics: integrative molecular classification and emerging treatments. Brain Sciences, 15:896, Aug 2025. URL: https://doi.org/10.3390/brainsci15080896, doi:10.3390/brainsci15080896. This article has 6 citations.
(ruggiero2026medulloblastomainadolescents pages 2-4): Antonio Ruggiero, Marco Gessi, Antonio d’Amati, Alessio Albanese, and Giorgio Attinà. Medulloblastoma in adolescents and young adults: molecular subgroups, prognostic biomarkers, and age-specific therapeutic challenges. Current Issues in Molecular Biology, 48:297, Mar 2026. URL: https://doi.org/10.3390/cimb48030297, doi:10.3390/cimb48030297. This article has 0 citations.
(korshunov2021integratedmolecularanalysis pages 1-2): Andrey Korshunov, Konstantin Okonechnikov, Damian Stichel, Marina Ryzhova, Daniel Schrimpf, Felix Sahm, Philipp Sievers, Oksana Absalyamova, Olga Zheludkova, Andrey Golanov, David T W Jones, Stefan M Pfister, Andreas von Deimling, and Marcel Kool. Integrated molecular analysis of adult sonic hedgehog (shh)-activated medulloblastomas reveals two clinically relevant tumor subsets with vegfa as potent prognostic indicator. Neuro-Oncology, 23:1576-1585, Feb 2021. URL: https://doi.org/10.1093/neuonc/noab031, doi:10.1093/neuonc/noab031. This article has 13 citations and is from a domain leading peer-reviewed journal.
(slika2023theneurodevelopmentaland pages 1-2): Hasan Slika, Paolo Alimonti, Divyaansh Raj, Chad Caraway, Safwan Alomari, Eric M. Jackson, and Betty Tyler. The neurodevelopmental and molecular landscape of medulloblastoma subgroups: current targets and the potential for combined therapies. Cancers, 15:3889, Jul 2023. URL: https://doi.org/10.3390/cancers15153889, doi:10.3390/cancers15153889. This article has 25 citations.
(korshunov2021integratedmolecularanalysis pages 2-3): Andrey Korshunov, Konstantin Okonechnikov, Damian Stichel, Marina Ryzhova, Daniel Schrimpf, Felix Sahm, Philipp Sievers, Oksana Absalyamova, Olga Zheludkova, Andrey Golanov, David T W Jones, Stefan M Pfister, Andreas von Deimling, and Marcel Kool. Integrated molecular analysis of adult sonic hedgehog (shh)-activated medulloblastomas reveals two clinically relevant tumor subsets with vegfa as potent prognostic indicator. Neuro-Oncology, 23:1576-1585, Feb 2021. URL: https://doi.org/10.1093/neuonc/noab031, doi:10.1093/neuonc/noab031. This article has 13 citations and is from a domain leading peer-reviewed journal.
(tonn2023riskpredictionin pages 1-2): Svenja Tonn, Andrey Korshunov, Denise Obrecht, Martin Sill, Michael Spohn, Katja von Hoff, Till Milde, Torsten Pietsch, Tobias Goschzik, Brigitte Bison, Björn-Ole Juhnke, Nina Struve, Dominik Sturm, Felix Sahm, Michael Bockmayr, Carsten Friedrich, André O von Bueren, Nicolas U Gerber, Martin Benesch, David T W Jones, Marcel Kool, Annika K Wefers, Ulrich Schüller, Stefan M Pfister, Stefan Rutkowski, and Martin Mynarek. Risk prediction in early childhood shh medulloblastoma treated with radiation-avoiding chemotherapy: evidence for more than two subgroups. Neuro-oncology, 25:1518-1529, Jan 2023. URL: https://doi.org/10.1093/neuonc/noad027, doi:10.1093/neuonc/noad027. This article has 8 citations and is from a domain leading peer-reviewed journal.
(tonn2023riskpredictionin pages 3-5): Svenja Tonn, Andrey Korshunov, Denise Obrecht, Martin Sill, Michael Spohn, Katja von Hoff, Till Milde, Torsten Pietsch, Tobias Goschzik, Brigitte Bison, Björn-Ole Juhnke, Nina Struve, Dominik Sturm, Felix Sahm, Michael Bockmayr, Carsten Friedrich, André O von Bueren, Nicolas U Gerber, Martin Benesch, David T W Jones, Marcel Kool, Annika K Wefers, Ulrich Schüller, Stefan M Pfister, Stefan Rutkowski, and Martin Mynarek. Risk prediction in early childhood shh medulloblastoma treated with radiation-avoiding chemotherapy: evidence for more than two subgroups. Neuro-oncology, 25:1518-1529, Jan 2023. URL: https://doi.org/10.1093/neuonc/noad027, doi:10.1093/neuonc/noad027. This article has 8 citations and is from a domain leading peer-reviewed journal.
(charton2024modellingtheeffects pages 13-17): C Charton. Modelling the effects of pediatric sonic hedgehog medulloblastoma driver mutations on granule lineage development. Unknown journal, 2024.
(pereira2021clinicalandmolecular pages 2-3): Victor Pereira, Jacob Torrejon, Dulanjalee Kariyawasam, Pablo Berlanga, Léa Guerrini-Rousseau, Olivier Ayrault, Pascale Varlet, Arnault Tauziède-Espariat, Stéphanie Puget, Stéphanie Bolle, Kevin Beccaria, Thomas Blauwblomme, Laurence Brugières, Jacques Grill, Birgit Geoerger, Christelle Dufour, and Samuel Abbou. Clinical and molecular analysis of smoothened inhibitors in sonic hedgehog medulloblastoma. Neuro-oncology Advances, Jul 2021. URL: https://doi.org/10.1093/noajnl/vdab097, doi:10.1093/noajnl/vdab097. This article has 26 citations and is from a peer-reviewed journal.
(tonn2023riskpredictionin media 3b1240bb): Svenja Tonn, Andrey Korshunov, Denise Obrecht, Martin Sill, Michael Spohn, Katja von Hoff, Till Milde, Torsten Pietsch, Tobias Goschzik, Brigitte Bison, Björn-Ole Juhnke, Nina Struve, Dominik Sturm, Felix Sahm, Michael Bockmayr, Carsten Friedrich, André O von Bueren, Nicolas U Gerber, Martin Benesch, David T W Jones, Marcel Kool, Annika K Wefers, Ulrich Schüller, Stefan M Pfister, Stefan Rutkowski, and Martin Mynarek. Risk prediction in early childhood shh medulloblastoma treated with radiation-avoiding chemotherapy: evidence for more than two subgroups. Neuro-oncology, 25:1518-1529, Jan 2023. URL: https://doi.org/10.1093/neuonc/noad027, doi:10.1093/neuonc/noad027. This article has 8 citations and is from a domain leading peer-reviewed journal.
(kim2025advancingmedulloblastomatherapy pages 10-12): David T. Kim, Michaela Uloho-Okundaye, Stephen C. Frederico, Santosh Guru, Min J. Kim, and Steven D. Chang. Advancing medulloblastoma therapy in pediatrics: integrative molecular classification and emerging treatments. Brain Sciences, 15:896, Aug 2025. URL: https://doi.org/10.3390/brainsci15080896, doi:10.3390/brainsci15080896. This article has 6 citations.
(pereira2021clinicalandmolecular pages 1-2): Victor Pereira, Jacob Torrejon, Dulanjalee Kariyawasam, Pablo Berlanga, Léa Guerrini-Rousseau, Olivier Ayrault, Pascale Varlet, Arnault Tauziède-Espariat, Stéphanie Puget, Stéphanie Bolle, Kevin Beccaria, Thomas Blauwblomme, Laurence Brugières, Jacques Grill, Birgit Geoerger, Christelle Dufour, and Samuel Abbou. Clinical and molecular analysis of smoothened inhibitors in sonic hedgehog medulloblastoma. Neuro-oncology Advances, Jul 2021. URL: https://doi.org/10.1093/noajnl/vdab097, doi:10.1093/noajnl/vdab097. This article has 26 citations and is from a peer-reviewed journal.
(NCT01601184 chunk 1): Study of Vismodegib in Combination With Temozolomide Versus Temozolomide Alone in Patients With Medulloblastomas With an Activation of the Sonic Hedgehog Pathway. Centre Leon Berard. 2012. ClinicalTrials.gov Identifier: NCT01601184
(NCT01125800 chunk 1): A Phase I Dose Finding and Safety Study of Oral LDE225 in Children and a Phase II Portion to Assess Preliminary Efficacy in Recurrent or Refractory MB. Novartis Pharmaceuticals. 2011. ClinicalTrials.gov Identifier: NCT01125800
(tonn2023riskpredictionin pages 2-3): Svenja Tonn, Andrey Korshunov, Denise Obrecht, Martin Sill, Michael Spohn, Katja von Hoff, Till Milde, Torsten Pietsch, Tobias Goschzik, Brigitte Bison, Björn-Ole Juhnke, Nina Struve, Dominik Sturm, Felix Sahm, Michael Bockmayr, Carsten Friedrich, André O von Bueren, Nicolas U Gerber, Martin Benesch, David T W Jones, Marcel Kool, Annika K Wefers, Ulrich Schüller, Stefan M Pfister, Stefan Rutkowski, and Martin Mynarek. Risk prediction in early childhood shh medulloblastoma treated with radiation-avoiding chemotherapy: evidence for more than two subgroups. Neuro-oncology, 25:1518-1529, Jan 2023. URL: https://doi.org/10.1093/neuonc/noad027, doi:10.1093/neuonc/noad027. This article has 8 citations and is from a domain leading peer-reviewed journal.
(kim2025advancingmedulloblastomatherapy pages 12-14): David T. Kim, Michaela Uloho-Okundaye, Stephen C. Frederico, Santosh Guru, Min J. Kim, and Steven D. Chang. Advancing medulloblastoma therapy in pediatrics: integrative molecular classification and emerging treatments. Brain Sciences, 15:896, Aug 2025. URL: https://doi.org/10.3390/brainsci15080896, doi:10.3390/brainsci15080896. This article has 6 citations.

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Classifications

Subtypes

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Treatments

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 Overview and current definition

1.2 Common synonyms / alternative names

1.3 Evidence source types

2. Etiology

2.1 Primary causal/mechanistic factors

2.2 Risk factors

Genetic risk factors

Environmental risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Clinical presentation (typical)

3.2 Age distribution and anatomic tendencies

3.3 HPO term suggestions (non-exhaustive)

4. Genetic / Molecular Information

4.1 Key causal/driver genes and alterations

4.2 DNA methylation / transcriptomic subclasses

4.3 Somatic vs germline

4.4 Epigenetics

5. Mechanism / Pathophysiology

5.1 Core pathway mechanism (causal chain)

5.2 Cell(s) of origin / lineage context

5.3 Suggested GO biological process terms

5.4 Suggested Cell Ontology (CL) terms

6. Inheritance and Population

6.1 Inheritance patterns (predisposition)

6.2 Epidemiology and subgroup proportions

7. Diagnostics

7.1 Integrated diagnosis approach

7.2 DNA methylation profiling (practical implementation)

7.3 Sequencing

7.4 Differential diagnosis

8. Outcome / Prognosis

8.1 Prognostic stratifiers

8.2 Early-childhood SHH prognosis under radiation-avoiding therapy (key statistics)

8.3 Adult SHH molecular subsets and prognosis

9. Treatment

9.1 Current standard backbone (real-world implementation)

9.2 Targeted therapy: SMO inhibitors (vismodegib, sonidegib)

Clinical activity and predictive biomarkers

Toxicities (key safety considerations)

Resistance mechanisms

9.3 Selected ClinicalTrials.gov implementations (NCTs)

9.4 MAXO (Medical Action Ontology) term suggestions

10. Prevention

10.1 Primary prevention

10.2 Secondary/tertiary prevention: predisposition recognition and therapy modification

11. Other Species / Natural Disease

12. Model Organisms / Experimental Models

Recent developments and “latest research” highlights (prioritizing 2023–2024)

Evidence summary table

Notes on gaps / limitations of this run