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Structure of IDH1-R132H PDB: 3MAR, adapted from Yang B et al. (2010) Cell Res.

C ancer Genomics and Metabolomics and Their Implications in Pathology and Oncology. isocitrate. Hai Yan Department of Pathology. R100. Structure of IDH1-R132H PDB: 3MAR, adapted from Yang B et al. (2010) Cell Res. R110. R132. Rogue Metabolism in Cancer:.

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Structure of IDH1-R132H PDB: 3MAR, adapted from Yang B et al. (2010) Cell Res.

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  1. Cancer Genomics and Metabolomics and Their Implications in Pathology and Oncology isocitrate Hai Yan Department of Pathology R100 Structure of IDH1-R132H PDB: 3MAR, adapted from Yang B et al. (2010) Cell Res. R110 R132

  2. Rogue Metabolism in Cancer: “The prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by aerobic glycolysis.”-Warburg

  3. Gliomas are a Major Health Challenge ~15,000 cases/year in the US, affects all ages Urgent need for new therapies anaplastic oligodendroglioma

  4. A Challenge WHO is HuaHua?

  5. Glioma Diagnosis is a Major Challenge • Secondary GBM • Median age ~45 • Arise from low- grade • Two different diseases! But… • They look the same! • And are treated the same! • Urgent need for new diagnosis Primary GBM • Median age ~60 • Arise de novo

  6. Isocitrate Dehydrogenase 1 (IDH1) and 2 (IDH2) are Frequently Mutated in Gliomas Parsons et al. Science 2008 Yan et al. NEJM 2009

  7. Patients with IDH Mutations are Younger • GBM without IDH mutations • Median age ~55 • GBM with IDH mutation • Median age ~30

  8. Patients with IDH Mutations Have a Better Survival Anaplastic astrocytoma GBM Patient Median Survival Mutated IDH: 65 months Wildtype IDH: 20 months Patient Median Survival Mutated IDH: 31 months Wildtype IDH: 14 months Yan et al. NEJM, 2009.

  9. IDH1 Mutant GBM from Distinct Cell of Origin Lai et al JCO 2011

  10. Glioma Pathogenesis CIC & FUBP

  11. IDH1 and IDH2 are Isocitrate Dehydrogenases Mitochondria Citrate Citrate Tricarboxylic acid cycle (TCA) Isocitrate Isocitrate NADP+ NAD+ NADP+ IDH2 IDH1 Cytosol IDH3 NADPH NADH NADPH α-ketoglutarate α-ketoglutarate Succinate Reitman and Yan (2010) J Natl Cancer Inst

  12. IDH1 and IDH2 Mutations Yan et al. NEJM 2009

  13. IDH1/2 Mutants Gain a Novel Enzyme Activity IDH1 WILD-TYPE Arg132Isocitrate β-carboxyl IDH1 MUTANT His132 α-ketoglutarate Dang et al. (2009) Nature Structures: Xu et al. (2004) J Biol Chem and Dang et al. (2009) Nature.

  14. IDH Mutations and 2-HG Production Cause Epigenetic Dysregulation nature medicine volume 17 | number 3 | MARCH 2011

  15. Tricarboxylic Acid (TCA) Cycle Metabolites Affected by IDH Mutant Expression or 2-HG Reitman, Jin et al., 2011, PNAS

  16. Rogue Metabolism in Cancer: Revisiting an old hypothesis and revolutionizing clinical genomics Diagnostic clarity Quick diagnostic access Improved prognosis Targeted therapy

  17. Lab Members and Collaborators • Yan Lab: Genglin Jin, Zach Reitman, Chris Duncan, Giselle Lopez, Pat Killela, Matt Wortham, Chris Pirozzi, Rui Yang, Lee Chen, Joey Webb, Jie Feng, Yu Wang • The Preston Robert Tisch Brain Tumor Center: Yiping He, Darell Bigner, Henry Friedman, Alan Friedman, Ivan Kos, Roger McLendon, Eric Lipp, Rasheed Ahmed, David Lister, Lisa Ehinger, Diane Satterfield • Johns Hopkins: Donald W. Parsons, Yuchen Jiao, Chetan Bettegowda, Victor Velculescu, Ken Kinzler, Nick Papadopolous, Luis Diaz, Bert Vogelstein

  18. Grant Support

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