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
• Názvy látek
• antigen Ki-67 MeSH
• CBFA2T2 myeloid-transforming gene-related protein MeSH Prohlížeč
• CBFA2T3 protein, human MeSH Prohlížeč
• core binding factor alpha MeSH Prohlížeč
• EOMES protein, human MeSH Prohlížeč
• histondemethylasy MeSH
• KDM6A protein, human MeSH Prohlížeč
• OTX2 protein, human MeSH Prohlížeč
• PRDM6 protein, human MeSH Prohlížeč
• proteiny hedgehog MeSH
• proteiny T-boxu MeSH
• represorové proteiny MeSH
• svalové proteiny MeSH
• transkripční faktory Otx MeSH
• transkripční faktory PEBP2A MeSH
• transkripční faktory MeSH

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC2-4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.

• MeSH
• DEAD-box RNA-helikasy genetika   MeSH
• DNA-topoisomerasy I genetika   MeSH
• germinální a embryonální nádory diagnóza   genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• mutace MeSH
• PARP inhibitory MeSH
• poly(ADP-ribosa)polymerasy genetika   MeSH
• recidiva MeSH
• ribonukleasa III genetika   MeSH
• RNA dlouhá nekódující MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• DEAD-box RNA-helikasy MeSH
• DICER1 protein, human MeSH Prohlížeč
• DNA-topoisomerasy I MeSH
• mikro RNA MeSH
• MIR17HG, human MeSH Prohlížeč
• PARP inhibitory MeSH
• poly(ADP-ribosa)polymerasy MeSH
• ribonukleasa III MeSH
• RNA dlouhá nekódující MeSH
• TOP1 protein, human MeSH Prohlížeč

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.

• Klíčová slova
• copy number, gene expression, integrative clustering, medulloblastoma, methylation, subgroups,
• 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
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

• MeSH
• buněčné klony účinky léků   metabolismus   patologie   MeSH
• cílená molekulární terapie metody   MeSH
• Drosophila melanogaster cytologie   genetika   MeSH
• genom lidský genetika   MeSH
• kraniospinální iradiace MeSH
• lidé MeSH
• lokální recidiva nádoru genetika   patologie   terapie   MeSH
• meduloblastom genetika   patologie   radioterapie   chirurgie   terapie   MeSH
• modely nemocí na zvířatech MeSH
• mutační analýza DNA MeSH
• myši MeSH
• nádory mozečku genetika   patologie   radioterapie   chirurgie   terapie   MeSH
• radioterapie řízená obrazem MeSH
• selekce (genetika) účinky léků   MeSH
• signální transdukce MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH