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.
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