Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.
- MeSH
- antigen Ki-67 metabolismus MeSH
- buněčná diferenciace * genetika MeSH
- buněčný rodokmen MeSH
- histondemethylasy MeSH
- lidé MeSH
- meduloblastom * klasifikace genetika patologie MeSH
- metencephalon * embryologie patologie MeSH
- mozeček embryologie patologie MeSH
- mutace MeSH
- nádory mozečku * klasifikace genetika patologie MeSH
- proteiny hedgehog metabolismus MeSH
- proteiny T-boxu metabolismus MeSH
- represorové proteiny MeSH
- svalové proteiny MeSH
- transkripční faktory Otx nedostatek genetika MeSH
- transkripční faktory PEBP2A genetika MeSH
- transkripční faktory MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
- MeSH
- dítě MeSH
- dospělí MeSH
- genetická variace MeSH
- genové regulační sítě MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- meduloblastom genetika MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádory mozečku genetika MeSH
- předškolní dítě MeSH
- proteiny hedgehog genetika MeSH
- regulace genové exprese u nádorů * MeSH
- signální transdukce genetika MeSH
- transkriptom * MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.
- MeSH
- genomika MeSH
- individualizovaná medicína * MeSH
- kohortové studie MeSH
- lidé MeSH
- meduloblastom klasifikace genetika terapie MeSH
- metylace DNA MeSH
- shluková analýza MeSH
- stanovení celkové genové exprese MeSH
- variabilita počtu kopií segmentů DNA MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. PATIENTS AND METHODS: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. RESULTS: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. CONCLUSION: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
- MeSH
- čipová analýza tkání MeSH
- cytogenetika MeSH
- dítě MeSH
- hodnocení rizik MeSH
- hybridizace in situ fluorescenční MeSH
- jaderné proteiny genetika MeSH
- kojenec MeSH
- lidé MeSH
- lidské chromozomy, pár 11 MeSH
- lidské chromozomy, pár 14 MeSH
- meduloblastom genetika mortalita patologie terapie MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádorové biomarkery genetika MeSH
- prediktivní hodnota testů MeSH
- předškolní dítě MeSH
- prognóza MeSH
- proporcionální rizikové modely MeSH
- proteiny hedgehog * genetika MeSH
- proteiny Wnt * genetika MeSH
- protoonkogenní proteiny c-myc genetika MeSH
- regulace genové exprese u nádorů MeSH
- reprodukovatelnost výsledků MeSH
- rizikové faktory MeSH
- stanovení celkové genové exprese MeSH
- transkripční faktory Krüppel-like genetika MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
