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Molecular diagnostics in pediatric glial tumors

Molecular diagnostics in pediatric glial tumors. Joon-Hyung Kim, MSIV Weill Cornell Medical College. Key molecular alterations in pediatric glial tumors. Anaplastic oligodendroglioma in adults (n=64). Progression Free Survival. Overall Survival. Snuderl et al. Clin Cancer Res 2009.

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Molecular diagnostics in pediatric glial tumors

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  1. Molecular diagnostics inpediatric glial tumors Joon-Hyung Kim, MSIV Weill Cornell Medical College

  2. Key molecular alterations in pediatric glial tumors

  3. Anaplastic oligodendroglioma in adults (n=64) Progression Free Survival Overall Survival Snuderlet al. Clin Cancer Res 2009.

  4. 1p and 19q deletions are infrequent in pediatric oligodendroglioma

  5. BRAF V600E in Ganglioglioma in Children MacConaill et al. 2009

  6. Schindler et al. 2011

  7. BRAF V600E in Ganglioglioma and Pleomorphic Xanthoastrocytoma in Children < 18 years • Initially described in melanoma, colon and papillary thyroid carcinoma • Vemurafenib (“V600Emutated BRAF inhibitor”) • FDA approved for late-stage or unresectable melanoma (Aug 2011)

  8. Unlike in adults, EGFR amplification, PTEN deletion, IDH1 mutations are rarely observed in pGBM.

  9. `

  10. H3F3A mutations are exclusive to high grade tumors and occur in the pediatric setting. H3F3A, ATRX, and DAXX mutations distinguish pediatric from adult GBM. Schwartzentruber et al., 2012

  11. H3F3A is located on chromosome 1q, a region of large-scale chromosomal gain in DIPG.

  12. Tumor-derived Exosomes • Exosomes are small membrane vesicles (30-100 nm) derived from luminal membranes of multivesicular bodies and released constitutively by fusion with cell membrane • Released from tumor cells, exosomes mediate local and systemic cell communication through horizontal transfer of information, such as mRNA, miRNA, proteins, DNA Electron microscopy of exosomes derived from U87 cells • Research questions: • 1. Can exosomes in peripheral blood of glioma patients serve as biomarkers of tumor progression? • 2. Can exosomes in patient plasma reliably predict parent tumor mutational status in brain? • -IDH1 R132H mutation • -BRAF V600E mutation

  13. DNA is present in tumor cell derived exosomes. ExoDNA exists predominantly as methylated, single stranded DNA exoDNA-1 exoDNA-2 gDNA S1 nuclease + - - - + + gDNA exoDNA DNase - + - + 10kb 3kb 10kb 1kb 3kb 1kb Anti-5’metCytosine Anti-DNA exoDNA gDNA Courtesy of Haiying Zhang and David Lyden

  14. Acknowledgements Neurosurgery • Jeffrey Greenfield, MD, PhD • Michael Kaplitt, MD, PhD • Philip Stieg, MD, PhD Pediatrics • David Lyden, MD, PhD Neurosurgery • Philip Gutin, MD Pathology • Jason Huse, MD, PhD Neuroradiology • Andrei Holodny, MD

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