Difference between revisions of "IDH mutation"

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*Cholangiocellular carcinoma<ref>{{Cite journal  | last1 = Zou | first1 = S. | last2 = Li | first2 = J. | last3 = Zhou | first3 = H. | last4 = Frech | first4 = C. | last5 = Jiang | first5 = X. | last6 = Chu | first6 = JS. | last7 = Zhao | first7 = X. | last8 = Li | first8 = Y. | last9 = Li | first9 = Q. | title = Mutational landscape of intrahepatic cholangiocarcinoma. | journal = Nat Commun | volume = 5 | issue =  | pages = 5696 | month = Dec | year = 2014 | doi = 10.1038/ncomms6696 | PMID = 25526346 }}</ref>
*Cholangiocellular carcinoma<ref>{{Cite journal  | last1 = Zou | first1 = S. | last2 = Li | first2 = J. | last3 = Zhou | first3 = H. | last4 = Frech | first4 = C. | last5 = Jiang | first5 = X. | last6 = Chu | first6 = JS. | last7 = Zhao | first7 = X. | last8 = Li | first8 = Y. | last9 = Li | first9 = Q. | title = Mutational landscape of intrahepatic cholangiocarcinoma. | journal = Nat Commun | volume = 5 | issue =  | pages = 5696 | month = Dec | year = 2014 | doi = 10.1038/ncomms6696 | PMID = 25526346 }}</ref>


===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.<ref>{{Cite journal  | last1 = Choi | first1 = C. | last2 = Raisanen | first2 = JM. | last3 = Ganji | first3 = SK. | last4 = Zhang | first4 = S. | last5 = McNeil | first5 = SS. | last6 = An | first6 = Z. | last7 = Madan | first7 = A. | last8 = Hatanpaa | first8 = KJ. | last9 = Vemireddy | first9 = V. | title = Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma. | journal = J Clin Oncol | volume = 34 | issue = 33 | pages = 4030-4039 | month = Nov | year = 2016 | doi = 10.1200/JCO.2016.67.1222 | PMID = 28248126 }}</ref>


===Implication===
===Implication===
*IDH mutant gliomas have a more favourable outcome than wildtype tumors<ref>{{Cite journal  | last1 = Hartmann | first1 = C. | last2 = Hentschel | first2 = B. | last3 = Wick | first3 = W. | last4 = Capper | first4 = D. | last5 = Felsberg | first5 = J. | last6 = Simon | first6 = M. | last7 = Westphal | first7 = M. | last8 = Schackert | first8 = G. | last9 = Meyermann | first9 = R. | title = 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. | journal = Acta Neuropathol | volume = 120 | issue = 6 | pages = 707-18 | month = Dec | year = 2010 | doi = 10.1007/s00401-010-0781-z | PMID = 21088844 }}</ref>
*IDH mutant gliomas have a more favourable outcome than wildtype tumors<ref>{{Cite journal  | last1 = Hartmann | first1 = C. | last2 = Hentschel | first2 = B. | last3 = Wick | first3 = W. | last4 = Capper | first4 = D. | last5 = Felsberg | first5 = J. | last6 = Simon | first6 = M. | last7 = Westphal | first7 = M. | last8 = Schackert | first8 = G. | last9 = Meyermann | first9 = R. | title = 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. | journal = Acta Neuropathol | volume = 120 | issue = 6 | pages = 707-18 | month = Dec | year = 2010 | doi = 10.1007/s00401-010-0781-z | PMID = 21088844 }}</ref>
*Within IDH mutant tumors, conventional grading is not represented by diffent survival.<ref>{{Cite journal  | last1 = Reuss | first1 = DE. | last2 = Mamatjan | first2 = Y. | last3 = Schrimpf | first3 = D. | last4 = Capper | first4 = D. | last5 = Hovestadt | first5 = V. | last6 = Kratz | first6 = A. | last7 = Sahm | first7 = F. | last8 = Koelsche | first8 = C. | last9 = Korshunov | first9 = A. | title = IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. | journal = Acta Neuropathol | volume = 129 | issue = 6 | pages = 867-73 | month = Jun | year = 2015 | doi = 10.1007/s00401-015-1438-8 | PMID = 25962792 }}</ref>
*Within IDH mutant tumors, conventional grading is not represented by diffent survival.<ref>{{Cite journal  | last1 = Reuss | first1 = DE. | last2 = Mamatjan | first2 = Y. | last3 = Schrimpf | first3 = D. | last4 = Capper | first4 = D. | last5 = Hovestadt | first5 = V. | last6 = Kratz | first6 = A. | last7 = Sahm | first7 = F. | last8 = Koelsche | first8 = C. | last9 = Korshunov | first9 = A. | title = IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. | journal = Acta Neuropathol | volume = 129 | issue = 6 | pages = 867-73 | month = Jun | year = 2015 | doi = 10.1007/s00401-015-1438-8 | PMID = 25962792 }}</ref>
*The IDH hotspot mutations result in increased 2-hydroxyglutarate which can be detected by Proton magnetic resonance spectroscopy.<ref>{{Cite journal | last1 = Choi | first1 = C. | last2 = Raisanen | first2 = JM. | last3 = Ganji | first3 = SK. | last4 = Zhang | first4 = S. | last5 = McNeil | first5 = SS. | last6 = An | first6 = Z. | last7 = Madan | first7 = A. | last8 = Hatanpaa | first8 = KJ. | last9 = Vemireddy | first9 = V. | title = Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma. | journal = J Clin Oncol | volume = 34 | issue = 33 | pages = 4030-4039 | month = Nov | year = 2016 | doi = 10.1200/JCO.2016.67.1222 | PMID = 28248126 }}</ref>
 
*IDH1 and IDH2 mutations are mutually exclusive.
*IDH2 mutations are more common in oligodendroglial tumors.   
   
   


Revision as of 10:23, 21 March 2018

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
  • Secondary Glioblastoma

Less common:

  • Myeloproliferative disorders[4]
  • Cholangiocellular carcinoma[5]

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.[6]

Implication

  • IDH mutant gliomas have a more favourable outcome than wildtype tumors[7]
  • Within IDH mutant tumors, conventional grading is not represented by diffent survival.[8]
  • 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.

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. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.

Neuropathology

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