Molecular Foundations of Paediatric Gliomas
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This document summarizes information on pediatric gliomas. It discusses how cancers arise from genetic and epigenetic aberrations, and outlines some of the major classes of cancer genes. It then focuses on pediatric brain tumors, noting that glioblastoma is a leading cause of cancer death in children. While the histology of pediatric glioblastoma is similar to the adult form, the molecular foundations differ. Specifically, pediatric glioblastomas often involve mutations in histone H3.3, ATRX, and DAXX. The document also summarizes key information on pediatric low-grade gliomas, molecular subgroups of pediatric high-grade gliomas, and opportunities for targeted therapies. It concludes by discussing the HeadSmart campaign in the
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Molecular Foundations of Paediatric Gliomas
- 2. Overview 1. Cancer as a disease of the genome 2. Paediatric brain tumours 3. Glioblastoma 4. Low-grade glioma 5. HeadSmart
- 3. • Cancer arises from the accumulation of Genetic aberrations • Epigenetic aberrations are also present • Together, they give rise to altered gene expression • Over 500 genes are now known to be involved in cancer 1. Cancer as a disease of the genome
- 4. If we know which genes are involved, we can: • Have a better understanding of cancer biology • Develop diagnostic and prognostic markers • Follow the clinical course • Develop targeted treatment
- 5. Major classes of cancer genes
- 7. Low mutation frequency in children’s cancer Strachan et al. Genetics & Genomics in Medicine (2015)
- 9. 2. Paediatric brain tumours • Leading cause of cancer-related death in children • Difficult to treat • Require interdisciplinary therapeu-c approach • Survivors can have long-term neurological, motor, hormonal, & cogni-ve impairment • Neuropathology moved from morphology-based approach to use of immunohistochemical & molecular markers • Biology star-ng to be understood from molecular studies • Targeted treatments emerging
- 10. Grade I Pilocytic astrocytoma Angiocentric glioma Grade II Diffuse astrocytoma Pilomyxoid astrocytoma Pleomorphic xanthoastrocytoma Grade III Anaplastic astrocytoma Grade IV Glioblastoma Overview of paediatric gliomas
- 11. 3. Paediatric glioblastoma • Highly malignant, diffusely infiltra-ng tumour • Leading cause of cancer-related death in children • 2-year survival ~12% • Histology similar to adult GBM • Molecular founda-ons are dis-nct from adult GBM Paediatric GBM Young adult GBM Adult GBM Adapted from E.H.Raabe et al, Cancer Cell 2012
- 17. Muta-ons in Histone H3.3 Lead to altered gene expression K27M G34R/V J. Schwartzentruber et al, Nature 2012, L. Bjerke et al, Cancer Research 2013 MYCN Global loss of H3K27m3 Sequestra-on of Polycomb EZH2 TP53 mut
- 18. Adapted from A.Korshunov et al, Acta Neuropathol 2015 Dis-nct molecular subgroups in paediatric high-grade glioma
- 19. Gajjar et al, JCO 2015 Dis-nct molecular subgroups in paediatric high-grade glioma
- 21. Pilocytic astrocytoma • Most common paediatric brain tumour • Typically in cerebellum or midline along hypothalamic/optic pathways • Well-circumscribed, non-invasive • Usually treated with surgery alone • Activating mutations in the MAPK signalling pathway (and PI3K) Diffuse astrocytoma • Infiltrating tumours • Occur throughout the CNS • Difficult to remove with surgery alone • Treated with radiation and chemotherapy • Activating mutations in the MAPK signalling pathway (and PI3K) • MYB mutations 4. Paediatric low-grade glioma
- 23. BRAF KIAA1549 KIAA1549-BRAF Transmembrane domain Ras-binding domain Cysteine-rich domain Kinase domain Glycine –rich loop Ac-va-on segment Fusion breakpoint T.Forshew et al, J. Pathol 2009; R.G.Tatevossian et al, J. Cell Physiol 2010 KIAA1549-BRAF fusion
- 25. Extracellular Signals Activation of the MAPK pathway BRAF MEK1/2 ERK1/2 RAS P P Prolifera4on NF1 Receptor Tyrosine Kinases
- 26. Activation of the MAPK pathway BRAF MEK1/2 ERK1/2 RAS P P Oncogene-Induced Senescence NF1 Receptor Tyrosine Kinases Extracellular Signals E.H.Raabe, Clin Cancer Res 2011; K.Jacob, Clin Cancer Res 2011
- 27. Whole genome sequencing of paediatric low-grade gliomas J.Zhang et al, Nature Genetics 2013
- 28. J.Zhang et al, Nature Genetics 2013 Whole genome sequencing of paediatric low-grade gliomas
- 29. KIAA1549-BRAF FAM131-BRAF FXR1-BRAF BRAF-MACF SRGAP3-RAF1 QKI-RAF1 BRAFv600e NF1-m FGFR1-TKD FGFR1-TACC1 FGFR1-TACC3 QKI-NTRK2 NACC2-NTRK2 Zhang et al, Nat Genetics 2013; Jones et al, Nat Genet 2013; Penman et al, Front Oncol 2015 Muta-ons in paediatric low-grade gliomas
- 30. Vemurafenib Dabrafenib Sorafenib Selumetinib Perifosine Perifosine MK2206 Rapamycin Everolimus PI-103 Bevacizumab Sorafenib Erlotinib VEGF VEGFR EGFR KIAA1549-BRAF FAM131-BRAF FXR1-BRAF BRAF-MACF SRGAP3-RAF1 QKI-RAF1 BRAFv600e NF1-m FGFR1-TKD FGFR1-TACC1 FGFR1-TACC3 QKI-NTRK2 NACC2-NTRK2 Zhang et al, Nat Genetics 2013; Jones et al, Nat Genet 2013; Penman et al, Front Oncol 2015 Opportuni-es for targeted therapy
- 31. M.A. Karajannis, Neuro-Oncology 2014 Opportuni-es for targeted therapy NCT01338857 Sorafenib ACCELERATED TUMOUR GROWTH!
- 32. Sorafenib trial: Accelerated tumour growth due to inhibi-on of senescence? BRAF MEK1/2 ERK1/2 RAS P P Oncogene-Induced Senescence NF1 Receptor Tyrosine Kinases E.H.Raabe, Clin Cancer Res 2011; K.Jacob, Clin Cancer Res 2011
- 37. 5. HeadSmart HeadSmart is a national campaign in the UK to raise awareness of the signs and symptoms of brain tumours in children and young people amongst the public and health professionals to reduce diagnosis times, reducing long-term disabilities and saving lives
- 38. Early diagnosis can improve the outcome – saving lives and reducing long-term disability
- 40. Why do delays in diagnosis occur? • Symptoms and signs mimic common, less serious disorders • Symptoms & signs are very varied – depending on their loca-on – depending on the age of the child – their severity can fluctuate • Childhood brain tumours are rela-vely rare – GPs will typically see only one, maybe two, childhood brain tumours in their whole career
- 41. Launch: June 2011 • Over 1.5 million Symptoms Cards distributed • Extensive media campaign • Almost 100,000 hits on website • Drama-c improvement in diagnos-c interval
- 43. David Walker: A new clinical guideline from the Royal College of Paediatrics and Child Health with a na-onal awareness campaign accelerates brain tumor diagnosis in UK children —“HeadSmart: Be Brain Tumour Aware” Neuro-Oncology 2015 Mean Diagnos4c Interval: Pre-campaign - 14 weeks May 2013 - 6.7 weeks