Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The implications of IDH mutations for cancer development and therapy

Abstract

Mutations in the genes encoding the cytoplasmic and mitochondrial forms of isocitrate dehydrogenase (IDH1 and IDH2, respectively; collectively referred to as IDH) are frequently detected in cancers of various origins, including but not limited to acute myeloid leukaemia (20%), cholangiocarcinoma (20%), chondrosarcoma (80%) and glioma (80%). In all cases, neomorphic activity of the mutated enzyme leads to production of the oncometabolite D-2-hydroxyglutarate, which has profound cell-autonomous and non-cell-autonomous effects. The broad effects of IDH mutations on epigenetic, differentiation and metabolic programmes, together with their high prevalence across a variety of cancer types, early presence in tumorigenesis and uniform expression in tumour cells, make mutant IDH an ideal therapeutic target. Herein, we describe the current biological understanding of IDH mutations and the roles of mutant IDH in the various associated cancers. We also present the available preclinical and clinical data on various methods of targeting IDH-mutant cancers and discuss, based on the underlying pathogenesis of different IDH-mutated cancer types, whether the treatment approaches will converge or be context dependent.

Key points

  • Mutations in IDH1 or IDH2 are frequent among several cancer types with various tissues of origin; the resultant mutated enzymes have neomorphic activity that leads to production of the oncometabolite D-2-hydroxyglutarate (D-2HG), which has profound effects on cellular epigenetic programmes, differentiation patterns and metabolic profiles.

  • The high prevalence of the IDH hotspot mutations, their occurrence early in tumorigenesis and the resulting uniform expression of the mutated protein in tumour cells make mutant isocitrate dehydrogenase (IDH) an appealing therapeutic target.

  • The roles of mutant IDH1 and IDH2 in cancer development and progression are probably transient or dynamic and context dependent.

  • IDH mutation status at disease recurrence can provide insights into their overall pathogenic role. In acute myeloid leukaemia, resistance mutations that restore the generation of D-2HG arise in response to inhibition of mutant IDH1 or IDH2, whereas recurrent gliomas often have a loss of heterozygosity of the affected IDH gene and decreased D-2HG production.

  • The greater efficacy of mutant IDH inhibitors against non-enhancing gliomas suggests that the timing of treatment with such agents is of crucial importance.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Prevalence and function of IDH mutations in cancers.

References

  1. 1.

    Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Hartmann, C. et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 118, 469–474 (2009).

    PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).

    Article  CAS  Google Scholar 

  6. 6.

    Marcucci, G. et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J. Clin. Oncol. 28, 2348–2355 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Borger, D. R. et al. Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping. Oncologist 17, 72–79 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Boscoe, A. N., Rolland, C. & Kelley, R. K. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J. Gastrointest. Oncol. 10, 751–765 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Amary, M. F. et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J. Pathol. 224, 334–343 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Dogan, S. et al. Frequent IDH2 R172 mutations in undifferentiated and poorly-differentiated sinonasal carcinomas. J. Pathol. 242, 400–408 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Guilmette, J. & Sadow, P. M. High-grade sinonasal carcinoma: classification through molecular profiling. Arch. Pathol. Lab. Med. 143, 1416–1419 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Mito, J. K. et al. Immunohistochemical detection and molecular characterization of IDH-mutant sinonasal undifferentiated carcinomas. Am. J. Surg. Pathol. 42, 1067–1075 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Cairns, R. A. et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood 119, 1901–1903 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Wang, C. et al. IDH2R172 mutations define a unique subgroup of patients with angioimmunoblastic T-cell lymphoma. Blood 126, 1741–1752 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Capper, D. et al. Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology. Acta Neuropathol. 121, 241–252 (2011).

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Watanabe, T., Nobusawa, S., Kleihues, P. & Ohgaki, H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am. J. Pathol. 174, 1149–1153 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Bleeker, F. E. et al. The prognostic IDH1(R132) mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma. Acta Neuropathol. 119, 487–494 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Xu, X. et al. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J. Biol. Chem. 279, 33946–33957 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Jin, G. et al. Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas. Cancer Res. 73, 496–501 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Jin, G. et al. 2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations. PLoS ONE 6, e16812 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Ward, P. S. et al. The potential for isocitrate dehydrogenase mutations to produce 2-hydroxyglutarate depends on allele specificity and subcellular compartmentalization. J. Biol. Chem. 288, 3804–3815 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Singh, A., Gurav, M., Dhanavade, S., Shetty, O. & Epari, S. Diffuse glioma — rare homozygous IDH point mutation, is it an oncogenetic mechanism? Neuropathology 37, 582–585 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Stancheva, G. et al. IDH1/IDH2 but Not TP53 mutations predict prognosis in bulgarian glioblastoma patients. Bio. Med. Res. Int. 2014, 654727 (2014).

    Google Scholar 

  25. 25.

    Zhao, S. et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha. Science 324, 261–265 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Mazor, T. et al. Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1. Proc. Natl Acad. Sci. USA 114, 10743–10748 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Luchman, H. A., Chesnelong, C., Cairncross, J. G. & Weiss, S. Spontaneous loss of heterozygosity leading to homozygous R132H in a patient-derived IDH1 mutant cell line. Neuro-oncology 15, 979–980 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Montalban-Bravo, G. & DiNardo, C. D. The role of IDH mutations in acute myeloid leukemia. Future Oncol. 14, 979–993 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Losman, J. A. & Kaelin, W. G. Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836–852 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Chowdhury, R. et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463–469 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Losman, J. A., Koivunen, P. & Kaelin, W. G. Jr. 2-Oxoglutarate-dependent dioxygenases in cancer. Nat. Rev. Cancer 20, 710–726 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Turcan, S. et al. Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nat. Genet. 50, 62–72 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Farshidfar, F. et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep. 18, 2780–2794 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Court, F. et al. Transcriptional alterations in glioma result primarily from DNA methylation-independent mechanisms. Genome Res. 29, 1605–1621 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Saha, S. K. et al. Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer. Nature 513, 110–114 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Jin, Y. et al. Mutant IDH1 dysregulates the differentiation of mesenchymal stem cells in association with gene-specific histone modifications to cartilage- and bone-related genes. PLoS ONE 10, e0131998 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44.

    Nagashima, H. et al. Poly(ADP-ribose) glycohydrolase inhibition sequesters NAD+ to potentiate the metabolic lethality of alkylating chemotherapy in IDH mutant tumor cells. Cancer Discov. 10, 1672–1689 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Tateishi, K. et al. The alkylating chemotherapeutic temozolomide induces metabolic stress in IDH1-mutant cancers and potentiates NAD+ depletion-mediated cytotoxicity. Cancer Res. 77, 4102–4115 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Tateishi, K. et al. Extreme vulnerability of IDH1 mutant cancers to NAD+ depletion. Cancer Cell 28, 773–784 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Esmaeili, M. et al. IDH1 R132H mutation generates a distinct phospholipid metabolite profile in glioma. Cancer Res. 74, 4898–4907 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Molenaar, R. J. et al. Radioprotection of IDH1-mutated cancer cells by the IDH1-mutant inhibitor AGI-5198. Cancer Res. 75, 4790–4802 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Gelman, S. J. et al. Consumption of NADPH for 2-HG synthesis increases pentose phosphate pathway flux and sensitizes cells to oxidative stress. Cell Rep. 22, 512–522 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Tran, A. N. et al. Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry. Neuro-Oncology 16, 414–420 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Yin, N. et al. IDH1-R132H mutation radiosensitizes U87MG glioma cells via epigenetic downregulation of TIGAR. Oncol. Lett. 19, 1322–1330 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Sulkowski, P. L. et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci. Transl. Med. 9, eaal2463 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    Sulkowski, P. L. et al. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature 582, 586–591 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Inoue, S. et al. Mutant IDH1 downregulates ATM and Alters DNA repair and sensitivity to DNA damage independent of TET2. Cancer Cell 30, 337–348 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Miller, J. J. et al. Sirtuin activation targets IDH-mutant tumors. Neuro-Oncology 23, 53–62 (2021).

    PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Lu, Y. et al. Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP1-mediated DNA repair. Cancer Res. 77, 1709–1718 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Burley, S. K. et al. RCSB Protein Data Bank: biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy. Nucleic Acids Res. 47, D464–D474 (2018).

    PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Ma, R. & Yun, C. H. Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2. Biochem. Biophys. Res. Commun. 503, 2912–2917 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Popovici-Muller, J. et al. Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo. ACS Med. Chem. Lett. 3, 850–855 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Urban, D. J. et al. Assessing inhibitors of mutant isocitrate dehydrogenase using a suite of pre-clinical discovery assays. Sci. Rep. 7, 12758 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Popovici-Muller, J. et al. Discovery of AG-120 (ivosidenib): a first-in-class mutant IDH1 inhibitor for the treatment of IDH1 mutant cancers. ACS Med. Chem. Lett. 9, 300–305 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Yen, K. et al. AG-221, a First-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 7, 478–493 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Konteatis, Z. et al. Vorasidenib (AG-881): a first-in-class, brain-penetrant dual inhibitor of mutant IDH1 and 2 for treatment of glioma. ACS Med. Chem. Lett. 11, 101–107 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Levell, J. R. et al. Optimization of 3-pyrimidin-4-yl-oxazolidin-2-ones as allosteric and mutant specific inhibitors of IDH1. ACS Med. Chem. Lett. 8, 151–156 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Pusch, S. et al. Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol. 133, 629–644 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. 67.

    Chaturvedi, A. et al. Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo. Leukemia 31, 2020–2028 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Cho, Y. S. et al. Discovery and evaluation of clinical candidate IDH305, a brain penetrant mutant IDH1 inhibitor. ACS Med. Chem. Lett. 8, 1116–1121 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Machida, Y. et al. A potent blood-brain barrier-permeable mutant IDH1 inhibitor suppresses the growth of glioblastoma with IDH1 mutation in a patient-derived orthotopic xenograft model. Mol. Cancer Ther. 19, 375–383 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Okoye-Okafor, U. C. et al. New IDH1 mutant inhibitors for treatment of acute myeloid leukemia. Nat. Chem. Biol. 11, 878–886 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Caravella, J. A. et al. Structure-based design and identification of FT-2102 (olutasidenib), a potent mutant-selective IDH1 inhibitor. J. Med. Chem. 63, 1612–1623 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Pauff, J. M. et al. A phase I study of LY3410738, a first-in-class covalent inhibitor of mutant IDH1 in cholangiocarcinoma and other advanced solid tumors. J. Clin. Oncol. 39, TPS350 (2021).

    Article  Google Scholar 

  73. 73.

    Stein, E. M. et al. A phase 1 study of LY3410738, a first-in-class covalent inhibitor of mutant IDH in advanced myeloid malignancies (trial in progress). Blood 136, 26 (2020).

    Article  Google Scholar 

  74. 74.

    Ferrara, F. & Schiffer, C. A. Acute myeloid leukaemia in adults. Lancet 381, 484–495 (2013).

    PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Walter, R. B. & Estey, E. H. Management of older or unfit patients with acute myeloid leukemia. Leukemia 29, 770–775 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Papaemmanuil, E. et al. Genomic classification and prognosis in acute myeloid leukemia. N. Engl. J. Med. 374, 2209–2221 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Stein, E. M. Molecular pathways: IDH2 mutations-co-opting cellular metabolism for malignant transformation. Clin. Cancer Res. 22, 16–19 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Green, C. L. et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood 118, 409–412 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    Xu, Q. et al. Correlation between isocitrate dehydrogenase gene aberrations and prognosis of patients with acute myeloid leukemia: a systematic review and meta-analysis. Clin. Cancer Res. 23, 4511–4522 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    DiNardo, C. D. et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am. J. Hematol. 90, 732–736 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Molenaar, R. J. et al. Clinical and biological implications of ancestral and non-ancestral IDH1 and IDH2 mutations in myeloid neoplasms. Leukemia 29, 2134–2142 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Morita, K. et al. Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics. Nat. Commun. 11, 5327 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Duncan, C. G. et al. A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation. Genome Res. 22, 2339–2355 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Stein, E. M. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130, 722–731 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Stein, E. M. et al. Enasidenib in patients with mutant IDH2 myelodysplastic syndromes: a phase 1 subgroup analysis of the multicentre, AG221-C-001 trial. Lancet Haematol. 7, e309–e319 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Stein, E. M. et al. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood 133, 676–687 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Fathi, A. T. et al. Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2: analysis of a phase 1/2 study. JAMA Oncol. 4, 1106–1110 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  88. 88.

    Amatangelo, M. D. et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 130, 732–741 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Roboz, G. J. et al. International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. J. Clin. Oncol. 32, 1919–1926 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Quek, L. et al. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib. Nat. Med. 24, 1167–1177 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Bunse, L. et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat. Med. 24, 1192–1203 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    DiNardo, C. D. et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N. Engl. J. Med. 378, 2386–2398 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  93. 93.

    Roboz, G. J. et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood 135, 463–471 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Choe, S. et al. Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML. Blood Adv. 4, 1894–1905 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Kantarjian, H. et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 106, 1090–1098 (2006).

    PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Heuser, M. et al. Safety and efficacy of BAY1436032 in IDH1-mutant AML: phase I study results. Leukemia 34, 2903–2913 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    DiNardo, C. D. et al. A phase I study of IDH305 in patients with advanced malignancies including relapsed/refractory AML and MDS that harbor IDH1R132 mutations. Blood 128, 1073–1073 (2016).

    Article  Google Scholar 

  98. 98.

    Harding, J. J. et al. Isoform switching as a mechanism of acquired resistance to mutant isocitrate dehydrogenase inhibition. Cancer Discov. 8, 1540–1547 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Intlekofer, A. M. et al. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 559, 125–129 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Terunuma, A. et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J. Clin. Invest. 124, 398–412 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  101. 101.

    Smolková, K., Dvorˇák, A., Zelenka, J., Vítek, L. & Ježek, P. Reductive carboxylation and 2-hydroxyglutarate formation by wild-type IDH2 in breast carcinoma cells. Int. J. Biochem. Cell Biol. 65, 125–133 (2015).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  102. 102.

    Wise, D. R. et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl Acad. Sci. USA 108, 19611–19616 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Chan, S. M. et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat. Med. 21, 178–184 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Lachowiez, C. A. et al. Phase Ib/II study of the IDH1-mutant inhibitor ivosidenib with the BCL2 inhibitor venetoclax +/− azacitidine in IDH1-mutated hematologic malignancies. J. Clin. Oncol. 38, 7500–7500 (2020).

    Article  Google Scholar 

  105. 105.

    DiNardo, C. D. et al. Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J. Clin. Oncol. 39, 57–65 (2021).

    PubMed  Article  PubMed Central  Google Scholar 

  106. 106.

    Banales, J. M. et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 17, 557–588 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Lee, K. et al. Intrahepatic cholangiocarcinomas with IDH1/2 mutation-associated hypermethylation at selective genes and their clinicopathological features. Sci. Rep. 10, 15820 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Wang, P. et al. Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas. Oncogene 32, 3091–3100 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Nakamura, H. et al. Genomic spectra of biliary tract cancer. Nat. Genet. 47, 1003–1010 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. 110.

    Pirozzi, C. J. et al. Mutant IDH1 disrupts the mouse subventricular zone and alters brain tumor progression. Mol. Cancer Res. 15, 507–520 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Sasaki, M. et al. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 26, 2038–2049 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Waitkus, M. S. et al. Adaptive evolution of the GDH2 allosteric domain promotes gliomagenesis by resolving IDH1R132H-induced metabolic liabilities. Cancer Res. 78, 36–50 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. 113.

    Amankulor, N. M. et al. Mutant IDH1 regulates the tumor-associated immune system in gliomas. Genes Dev. 31, 774–786 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Ding, N. et al. Oncogenic potential of IDH1R132C mutant in cholangiocarcinoma development in mice. World J. Gastroenterol. 22, 2071–2080 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Jusakul, A. et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov. 7, 1116–1135 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Saha, S. K. et al. Isocitrate dehydrogenase mutations confer dasatinib hypersensitivity and SRC dependence in intrahepatic cholangiocarcinoma. Cancer Discov. 6, 727–739 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Lowery, M. A. et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol. Hepatol. 4, 711–720 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Abou-Alfa, G. K. et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 21, 796–807 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Meijer, D. et al. Genetic characterization of mesenchymal, clear cell, and dedifferentiated chondrosarcoma. Genes Chromosomes Cancer 51, 899–909 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  120. 120.

    Bovée, J. V., Hogendoorn, P. C., Wunder, J. S. & Alman, B. A. Cartilage tumours and bone development: molecular pathology and possible therapeutic targets. Nat. Rev. Cancer 10, 481–488 (2010).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  121. 121.

    Nicolle, R. et al. Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression. Nat. Commun. 10, 4622 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  122. 122.

    Hirata, M. et al. Mutant IDH is sufficient to initiate enchondromatosis in mice. Proc. Natl Acad. Sci. USA 112, 2829–2834 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Li, L. et al. Treatment with a small molecule mutant IDH1 inhibitor suppresses tumorigenic activity and decreases production of the oncometabolite 2-hydroxyglutarate in human chondrosarcoma cells. PLoS ONE 10, e0133813 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. 124.

    Suijker, J. et al. Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines. Oncotarget 6, 12505–12519 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Li, L. et al. Mutant IDH1 depletion downregulates integrins and impairs chondrosarcoma growth. Cancers 12, 141 (2020).

    CAS  PubMed Central  Article  Google Scholar 

  126. 126.

    Nakagawa, M. et al. Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma. Oncogene 38, 6835–6849 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. 127.

    Cleven, A. H. G. et al. IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas. Clin. Sarcoma Res. 7, 8 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  128. 128.

    Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N. Engl. J. Med. 372, 2481–2498 (2015).

    Article  CAS  Google Scholar 

  129. 129.

    Zhu, G. G. et al. Genomic profiling identifies association of IDH1/IDH2 mutation with longer relapse-free and metastasis-free survival in high-grade chondrosarcoma. Clin. Cancer Res. 26, 419–427 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. 130.

    Tap, W. D. et al. Phase I study of the mutant IDH1 inhibitor ivosidenib: safety and clinical activity in patients with advanced chondrosarcoma. J. Clin. Oncol. 38, 1693–1701 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013-2017. Neuro-Oncology 22, iv1–iv96 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  132. 132.

    Jiao, Y. et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3, 709–722 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Ceccarelli, M. et al. Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma. Cell 164, 550–563 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Chaudhry, F. A. et al. Glutamine uptake by neurons: interaction of protons with system a transporters. J. Neurosci. 22, 62–72 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Ohka, F. et al. Quantitative metabolome analysis profiles activation of glutaminolysis in glioma with IDH1 mutation. Tumor Biol. 35, 5911–5920 (2014).

    CAS  Article  Google Scholar 

  137. 137.

    Ruiz-Rodado, V. et al. Metabolic plasticity of IDH1-mutant glioma cell lines is responsible for low sensitivity to glutaminase inhibition. Cancer Metab. 8, 23 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Seltzer, M. J. et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 70, 8981–8987 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Barthel, F. P. et al. Longitudinal molecular trajectories of diffuse glioma in adults. Nature 576, 112–120 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Touat, M. et al. Mechanisms and therapeutic implications of hypermutation in gliomas. Nature 580, 517–523 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Kohanbash, G. et al. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas. J. Clin. Invest. 127, 1425–1437 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Mu, L. et al. The IDH1 mutation-induced oncometabolite, 2-hydroxyglutarate, may affect DNA methylation and expression of PD-L1 in gliomas. Front. Mol. Neurosci. 11, 82 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  145. 145.

    Berghoff, A. S. et al. Correlation of immune phenotype with IDH mutation in diffuse glioma. Neuro-Oncology 19, 1460–1468 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Garber, S. T. et al. Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies. Neuro-Oncology18, 1357–1366 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Hodges, T. R. et al. Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro-Oncology 19, 1047–1057 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Kadiyala, P. et al. Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice. J. Clin. Invest. 131, e39542 (2021).

    Article  Google Scholar 

  149. 149.

    Grabowski, M. M. et al. Immune suppression in gliomas. J. Neurooncol. 151, 3–12 (2021).

    PubMed  Article  PubMed Central  Google Scholar 

  150. 150.

    Unruh, D. et al. Methylation and transcription patterns are distinct in IDH mutant gliomas compared to other IDH mutant cancers. Sci. Rep. 9, 8946 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. 151.

    Zhang, X. et al. IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression. Neuro-Oncology 18, 1402–1412 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Schumacher, T. et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324–327 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  153. 153.

    Biedermann, J. et al. Mutant IDH1 differently affects redox state and metabolism in glial cells of normal and tumor origin. Cancers 11, 2028 (2019).

    CAS  PubMed Central  Article  Google Scholar 

  154. 154.

    Tiburcio, P. D. B., Gillespie, D. L., Jensen, R. L. & Huang, L. E. Extracellular glutamate and IDH1(R132H) inhibitor promote glioma growth by boosting redox potential. J. Neurooncol. 146, 427–437 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Arvanitis, C. D., Ferraro, G. B. & Jain, R. K. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat. Rev. Cancer 20, 26–41 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  156. 156.

    Mellinghoff, I. K. et al. Ivosidenib in isocitrate dehydrogenase 1-mutated advanced glioma. J. Clin. Oncol. 38, 3398–3406 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  157. 157.

    Tejera, D. et al. Ivosidenib, an IDH1 inhibitor, in a patient with recurrent, IDH1-mutant glioblastoma: a case report from a phase I study. CNS Oncol. 9, Cns62 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Andronesi, O. C. et al. Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate. Nat. Commun. 9, 1474 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  159. 159.

    Stresemann, C. & Lyko, F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer 123, 8–13 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    Turcan, S. et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine. Oncotarget 4, 1729–1736 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Borodovsky, A. et al. 5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft. Oncotarget 4, 1737–1747 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Yamashita, A. S. et al. Demethylation and epigenetic modification with 5-azacytidine reduces IDH1 mutant glioma growth in combination with temozolomide. Neuro-Oncology 21, 189–200 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  163. 163.

    Bunse, L. et al. Proximity ligation assay evaluates IDH1R132H presentation in gliomas. J. Clin. Invest. 125, 593–606 (2015).

    PubMed  PubMed Central  Google Scholar 

  164. 164.

    Platten, M. et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature 592, 463–468 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. 165.

    Schlesinger, Y. et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat. Genet. 39, 232–236 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  166. 166.

    Sørensen, A. L., Jacobsen, B. M., Reiner, A. H., Andersen, I. S. & Collas, P. Promoter DNA methylation patterns of differentiated cells are largely programmed at the progenitor stage. Mol. Biol. Cell 21, 2066–2077 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  167. 167.

    Widschwendter, M. et al. Epigenetic stem cell signature in cancer. Nat. Genet. 39, 157–158 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  168. 168.

    Ohm, J. E. et al. A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat. Genet. 39, 237–242 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Stein, E. M. et al. Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study. Blood 137, 1792–1803 (2020).

    Article  CAS  Google Scholar 

  170. 170.

    Watts, J. M. et al. A phase 1 dose escalation study of the IDH1m inhibitor, FT-2102, in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). J. Clin. Oncol. 36, 7009–7009 (2018).

    Article  Google Scholar 

Download references

Acknowledgements

The work of C.J.P. has been supported by the Hope Funds for Cancer Research. The authors thank L. Chen, P. K. Greer, N. M. Reynolds and K. Brooks Roso, of Duke University, for critical editorial review, support and guidance with data representation.

Author information

Affiliations

Authors

Contributions

C.J.P. researched data for the article and wrote the manuscript. Both authors made substantial contributions to the discussion of content and reviewed/edited the manuscript before submission.

Corresponding authors

Correspondence to Christopher J. Pirozzi or Hai Yan.

Ethics declarations

Competing interests

H.Y. is the chief scientific officer and has ownership interest in Genetron Holdings and receives royalties from Agios, Genetron and Personal Genome Diagnostics (PGDX). H.Y. holds a patent related to genetic alterations in IDH and other genes in malignant glioma (US Patent 8,685,660B2) issued, licensed and with royalties paid by Agios; a patent for genetic alterations in IDH and other genes in malignant glioma issued, licensed and with royalties paid by PGDX; a patent on methods for the rapid and sensitive detection of hotspot mutations (US 10,633,711B2) issued, licensed and with royalties paid by Genetron Holdings; a patent on homozygous and heterozygous IDH1 gene-defective human astrocytoma cell lines (US 9,695,400B2); and a patent on homozygous and heterozygous IDH1 gene-defective cell lines derived from human colorectal cells (US 9,074,221B2). C.J.P. declares no competing interests.

Additional information

Peer review information

Nature Reviews Clinical Oncology thanks Amir T. Fathi, Pim French, Tak W. Mak and Sevin Turcan for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

RCSB PDB 6ADG: https://www.rcsb.org/structure/6ADG

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pirozzi, C.J., Yan, H. The implications of IDH mutations for cancer development and therapy. Nat Rev Clin Oncol 18, 645–661 (2021). https://doi.org/10.1038/s41571-021-00521-0

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing