IDH mutation

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IDH mutation is a re-occuring theme in molecular neuropathology. IDH is an oncometabolite. Mutations are located at hotspot positions in IDH R132, IDH2 R140 or IDH2 R172.[1] [2]

General

Seen in:[3]

  • Astrocytoma.
  • Oligodendroglioma (requirement for diagnosis).
  • Secondary Glioblastoma.
    • Ddx: IDH mutations in PNET are most likely misdiagnosed small cell glioblastomas.[4]


Less common:

  • Myeloproliferative disorders[5]
  • Cholangiocellular carcinoma[6][7]
  • Esthesioneuroblastoma.[8]
    • DDx: Sinunasal undifferentiated carcinoma.[9]
  • Malignant melanoma.[10]

Molecular background

  • IDH are present as homodimers and oxidize isocitrate to alpha-ketoglutarate.
  • Heterozygous IDH mutations result in reduction of alpha-ketoglutrate to D-2-hydroxyglutarate.
  • D-2-hydroxyglutarate blocks histone demethylation and promotes proliferation.
  • The increased D-2-hydroxyglutarate can be detected by Proton magnetic resonance spectroscopy.[11]

Implication

  • IDH mutant gliomas have a more favourable outcome than wildtype tumors[12]
  • Within IDH mutant tumors, conventional grading is not represented by diffent survival.[13]
  • IDH1 and IDH2 mutations are mutually exclusive.
  • IDH2 mutations are more common in oligodendroglial tumors.


Diagnosis

  • (Pyro)sequencing of exon4 IDH1/2
  • Mutation-specific antibody for the most common IDH-1 R132H mutation available.
  • IDH1 mutations are far more common than IDH2 mutations in glioma.

See also

References

  1. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 147700
  2. ↑ Online 'Mendelian Inheritance in Man' (OMIM) 147650
  3. ↑ Capper, D.; Reuss, D.; Schittenhelm, J.; Hartmann, C.; Bremer, J.; Sahm, F.; Harter, PN.; Jeibmann, A. et al. (Feb 2011). "Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology.". Acta Neuropathol 121 (2): 241-52. doi:10.1007/s00401-010-0770-2. PMID 21069360.
  4. ↑ Song, X.; Andrew Allen, R.; Terence Dunn, S.; Fung, KM.; Farmer, P.; Gandhi, S.; Ranjan, T.; Demopoulos, A. et al. (2011). "Glioblastoma with PNET-like components has a higher frequency of isocitrate dehydrogenase 1 (IDH1) mutation and likely a better prognosis than primary glioblastoma.". Int J Clin Exp Pathol 4 (7): 651-60. PMID 22076165.
  5. ↑ Andrulis, M.; Capper, D.; Luft, T.; Hartmann, C.; Zentgraf, H.; von Deimling, A. (Aug 2010). "Detection of isocitrate dehydrogenase 1 mutation R132H in myelodysplastic syndrome by mutation-specific antibody and direct sequencing.". Leuk Res 34 (8): 1091-3. doi:10.1016/j.leukres.2010.02.014. PMID 20227112.
  6. ↑ Zou, S.; Li, J.; Zhou, H.; Frech, C.; Jiang, X.; Chu, JS.; Zhao, X.; Li, Y. et al. (Dec 2014). "Mutational landscape of intrahepatic cholangiocarcinoma.". Nat Commun 5: 5696. doi:10.1038/ncomms6696. PMID 25526346.
  7. ↑ Farshidfar, F.; Zheng, S.; Gingras, MC.; Newton, Y.; Shih, J.; Robertson, AG.; Hinoue, T.; Hoadley, KA. et al. (03 2017). "Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.". Cell Rep 18 (11): 2780-2794. doi:10.1016/j.celrep.2017.02.033. PMID 28297679.
  8. ↑ Capper, D.; Engel, NW.; Stichel, D.; Lechner, M.; Glöss, S.; Schmid, S.; Koelsche, C.; Schrimpf, D. et al. (08 2018). "DNA methylation-based reclassification of olfactory neuroblastoma.". Acta Neuropathol 136 (2): 255-271. doi:10.1007/s00401-018-1854-7. PMID 29730775.
  9. ↑ Dogan, S.; Chute, DJ.; Xu, B.; Ptashkin, RN.; Chandramohan, R.; Casanova-Murphy, J.; Nafa, K.; Bishop, JA. et al. (08 2017). "Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas.". J Pathol 242 (4): 400-408. doi:10.1002/path.4915. PMID 28493366.
  10. ↑ Linos, K.; Tafe, LJ. (Dec 2018). "Isocitrate dehydrogenase 1 mutations in melanoma frequently co-occur with NRAS mutations.". Histopathology 73 (6): 963-968. doi:10.1111/his.13707. PMID 30003571.
  11. ↑ Choi, C.; Raisanen, JM.; Ganji, SK.; Zhang, S.; McNeil, SS.; An, Z.; Madan, A.; Hatanpaa, KJ. et al. (Nov 2016). "Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma.". J Clin Oncol 34 (33): 4030-4039. doi:10.1200/JCO.2016.67.1222. PMID 28248126.
  12. ↑ Hartmann, C.; Hentschel, B.; Wick, W.; Capper, D.; Felsberg, J.; Simon, M.; Westphal, M.; Schackert, G. et al. (Dec 2010). "Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas.". Acta Neuropathol 120 (6): 707-18. doi:10.1007/s00401-010-0781-z. PMID 21088844.
  13. ↑ Reuss, DE.; Mamatjan, Y.; Schrimpf, D.; Capper, D.; Hovestadt, V.; Kratz, A.; Sahm, F.; Koelsche, C. et al. (Jun 2015). "IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO.". Acta Neuropathol 129 (6): 867-73. doi:10.1007/s00401-015-1438-8. PMID 25962792.
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