Difference between revisions of "IDH mutation"

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==General==
==General==
Seen in:<ref>{{Cite journal  | last1 = Capper | first1 = D. | last2 = Reuss | first2 = D. | last3 = Schittenhelm | first3 = J. | last4 = Hartmann | first4 = C. | last5 = Bremer | first5 = J. | last6 = Sahm | first6 = F. | last7 = Harter | first7 = PN. | last8 = Jeibmann | first8 = A. | last9 = von Deimling | first9 = A. | title = Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology. | journal = Acta Neuropathol | volume = 121 | issue = 2 | pages = 241-52 | month = Feb | year = 2011 | doi = 10.1007/s00401-010-0770-2 | PMID = 21069360 }}</ref>
Seen in:<ref>{{Cite journal  | last1 = Capper | first1 = D. | last2 = Reuss | first2 = D. | last3 = Schittenhelm | first3 = J. | last4 = Hartmann | first4 = C. | last5 = Bremer | first5 = J. | last6 = Sahm | first6 = F. | last7 = Harter | first7 = PN. | last8 = Jeibmann | first8 = A. | last9 = von Deimling | first9 = A. | title = Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology. | journal = Acta Neuropathol | volume = 121 | issue = 2 | pages = 241-52 | month = Feb | year = 2011 | doi = 10.1007/s00401-010-0770-2 | PMID = 21069360 }}</ref>
*Astrocytoma
*Astrocytoma.
*Oligodendroglioma
*Oligodendroglioma (requirement for diagnosis).<ref>{{Cite journal  | last1 = Wesseling | first1 = P. | last2 = Capper | first2 = D. | title = WHO 2016 Classification of gliomas. | journal = Neuropathol Appl Neurobiol | volume = 44 | issue = 2 | pages = 139-150 | month = 02 | year = 2018 | doi = 10.1111/nan.12432 | PMID = 28815663 }}</ref>
*Secondary Glioblastoma
*Secondary Glioblastoma.
**DDx: IDH mutations in PNET are most likely misdiagnosed small cell glioblastomas.<ref>{{Cite journal  | last1 = Song | first1 = X. | last2 = Andrew Allen | first2 = R. | last3 = Terence Dunn | first3 = S. | last4 = Fung | first4 = KM. | last5 = Farmer | first5 = P. | last6 = Gandhi | first6 = S. | last7 = Ranjan | first7 = T. | last8 = Demopoulos | first8 = A. | last9 = Symons | first9 = M. | title = Glioblastoma with PNET-like components has a higher frequency of isocitrate dehydrogenase 1 (IDH1) mutation and likely a better prognosis than primary glioblastoma. | journal = Int J Clin Exp Pathol | volume = 4 | issue = 7 | pages = 651-60 | month =  | year = 2011 | doi =  | PMID = 22076165 }}</ref>
 
 


Less common:
Less common:
*Myeloproliferative disorders<ref>{{Cite journal  | last1 = Andrulis | first1 = M. | last2 = Capper | first2 = D. | last3 = Luft | first3 = T. | last4 = Hartmann | first4 = C. | last5 = Zentgraf | first5 = H. | last6 = von Deimling | first6 = A. | title = Detection of isocitrate dehydrogenase 1 mutation R132H in myelodysplastic syndrome by mutation-specific antibody and direct sequencing. | journal = Leuk Res | volume = 34 | issue = 8 | pages = 1091-3 | month = Aug | year = 2010 | doi = 10.1016/j.leukres.2010.02.014 | PMID = 20227112 }}</ref>
*Myeloproliferative disorders<ref>{{Cite journal  | last1 = Andrulis | first1 = M. | last2 = Capper | first2 = D. | last3 = Luft | first3 = T. | last4 = Hartmann | first4 = C. | last5 = Zentgraf | first5 = H. | last6 = von Deimling | first6 = A. | title = Detection of isocitrate dehydrogenase 1 mutation R132H in myelodysplastic syndrome by mutation-specific antibody and direct sequencing. | journal = Leuk Res | volume = 34 | issue = 8 | pages = 1091-3 | month = Aug | year = 2010 | doi = 10.1016/j.leukres.2010.02.014 | PMID = 20227112 }}</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>
*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><ref>{{Cite journal  | last1 = Farshidfar | first1 = F. | last2 = Zheng | first2 = S. | last3 = Gingras | first3 = MC. | last4 = Newton | first4 = Y. | last5 = Shih | first5 = J. | last6 = Robertson | first6 = AG. | last7 = Hinoue | first7 = T. | last8 = Hoadley | first8 = KA. | last9 = Gibb | first9 = EA. | title = Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles. | journal = Cell Rep | volume = 18 | issue = 11 | pages = 2780-2794 | month = 03 | year = 2017 | doi = 10.1016/j.celrep.2017.02.033 | PMID = 28297679 }}</ref>
*Esthesioneuroblastoma.<ref>{{Cite journal  | last1 = Capper | first1 = D. | last2 = Engel | first2 = NW. | last3 = Stichel | first3 = D. | last4 = Lechner | first4 = M. | last5 = Glöss | first5 = S. | last6 = Schmid | first6 = S. | last7 = Koelsche | first7 = C. | last8 = Schrimpf | first8 = D. | last9 = Niesen | first9 = J. | title = DNA methylation-based reclassification of olfactory neuroblastoma. | journal = Acta Neuropathol | volume = 136 | issue = 2 | pages = 255-271 | month = 08 | year = 2018 | doi = 10.1007/s00401-018-1854-7 | PMID = 29730775 }}</ref>
**DDx: Sinunasal undifferentiated carcinoma.<ref>{{Cite journal  | last1 = Dogan | first1 = S. | last2 = Chute | first2 = DJ. | last3 = Xu | first3 = B. | last4 = Ptashkin | first4 = RN. | last5 = Chandramohan | first5 = R. | last6 = Casanova-Murphy | first6 = J. | last7 = Nafa | first7 = K. | last8 = Bishop | first8 = JA. | last9 = Chiosea | first9 = SI. | title = Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas. | journal = J Pathol | volume = 242 | issue = 4 | pages = 400-408 | month = 08 | year = 2017 | doi = 10.1002/path.4915 | PMID = 28493366 }}</ref>
*Malignant melanoma.<ref>{{Cite journal  | last1 = Linos | first1 = K. | last2 = Tafe | first2 = LJ. | title = Isocitrate dehydrogenase 1 mutations in melanoma frequently co-occur with NRAS mutations. | journal = Histopathology | volume = 73 | issue = 6 | pages = 963-968 | month = Dec | year = 2018 | doi = 10.1111/his.13707 | PMID = 30003571 }}</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.   
   
   


===Diagnosis===
===Diagnosis===
*(Pyro)sequencing of exon4 IDH1/2
*(Pyro)sequencing of exon4 IDH1/2
*Mutation-specific antibody for the most common [[IDH-1]] R132H mutation.
* 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==
==See also==
Line 29: Line 43:
{{Reflist|1}}
{{Reflist|1}}


[[Category:Molecular pathology]][[Neuropathology]]
[[Category:Molecular pathology]][[Category:Neuropathology]]

Latest revision as of 12:58, 22 October 2019

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).[4]
  • Secondary Glioblastoma.
    • DDx: IDH mutations in PNET are most likely misdiagnosed small cell glioblastomas.[5]


Less common:

  • Myeloproliferative disorders[6]
  • Cholangiocellular carcinoma[7][8]
  • Esthesioneuroblastoma.[9]
    • DDx: Sinunasal undifferentiated carcinoma.[10]
  • Malignant melanoma.[11]

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.[12]

Implication

  • IDH mutant gliomas have a more favourable outcome than wildtype tumors[13]
  • Within IDH mutant tumors, conventional grading is not represented by diffent survival.[14]
  • 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. Wesseling, P.; Capper, D. (02 2018). "WHO 2016 Classification of gliomas.". Neuropathol Appl Neurobiol 44 (2): 139-150. doi:10.1111/nan.12432. PMID 28815663.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.