Untangling the role
of IDH in Oncology

Mutations in IDH drive cancer progression
via epigenetic dysregulation – high-level
changes in methylation altering chromatin
structure, blocking cellular differentiation,
and ultimately driving oncogenesis.1

Mutations in IDH drive cancer progression via epigenetic dysregulation – high-level changes in methylation altering chromatin structure, blocking cellular differentiation, and ultimately driving oncogenesis.1

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What is IDH?

Thumbnail, click for more info: Isocitrate dehydrogenase 1 and 2

Isocitrate dehydrogenase 1 and 2 (IDH1) and (IDH2) are enzymes critical for the conversion of isocitrate to α-ketoglutarate (α-KG), a key functional metabolite.1 Mutations in IDH genes result in increased concentrations of the related oncometabolite 2-hydroxyglutarate (2-HG), which blocks the action of α-KG, interfering with the epigenetic regulation of numerous oncogenic processes and promoting an immunosuppressive tumor microenvironment.1,2

Mutations in IDH1 and IDH2 are observed in a variety of
cancers, including acute myeloid leukemia (AML),
myelodysplastic syndromes (MDS), IDH-mutant glioma, and
cholangiocarcinoma, reinforcing a key pathogenetic role for
these mutations.1

Isocitrate dehydrogenase 1 and 2 (IDH1) and (IDH2) are enzymes critical for the conversion of isocitrate to α-ketoglutarate (α-KG), a key functional metabolite.1 Mutations in IDH genes result in increased concentrations of the related oncometabolite 2-hydroxyglutarate (2-HG), which blocks the action of α-KG, interfering with the epigenetic regulation of numerous oncogenic processes and promoting an immunosuppressive tumor microenvironment.1,2

Mutations in IDH1 and IDH2 are observed in a variety of cancers, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), IDH-mutant glioma, and cholangiocarcinoma, reinforcing a key pathogenetic role for these mutations.1

IDH mutations cause overarching metabolic reprogramming
that results in dysregulation of1:

Icon: Gene expression

Gene expression

Icon: Intracellular trafficking

Intracellular trafficking

Icon: DNA damage repair

DNA damage repair

Icon: Aging

Aging

Icon: Inflammation

Inflammation

Icon: Cell death

Cell death

Explore video clips on the function of IDH1 and the impact of mutation1,4–7

Overview of IDH1 and mutated IDH1 (mIDH1) (video)

Overview of IDH1 and mutated IDH1 (mIDH1)

What is the normal function of IDH1? (video)

What is the normal function of IDH1?

What is the impact of mIDH1? (video)

What is the impact of mIDH1?

The Negative Impact of mIDH
in MDS and AML

The Negative Impact of mIDH in MDS and AML

Due to the overarching roles in gene regulation, mutations in IDH, especially IDH1, can lead to worse outcomes, in both MDS and AML.8–11

Although the full prognostic significance of IDH mutations is still being established, existing data indicates that patients with IDH1 mutations are more often in adverse risk categories and may have worse overall outcomes than those with IDH wild-type.9–11

Furthermore, IDH1 mutations are considered early “driver” mutations in the progression of MDS, as MDS-to-AML transformation occurs at a higher rate in patients with IDH1 mutations.11–13

Due to the overarching roles in gene regulation, mutations in IDH, especially IDH1, can lead to worse outcomes, in both MDS and AML.8–11

Although the full prognostic significance of IDH mutations is still being established, existing data indicates that patients with IDH1 mutations are more often in adverse risk categories and may have worse overall outcomes than those with IDH wild-type.9–11

Furthermore, IDH1 mutations are considered early “driver” mutations in the progression of MDS, as MDS-to-AML transformation occurs at a higher rate in patients with IDH1 mutations.11–13

Thumbnail, click for more info. Kaplan-Meier curves for overall and event-free survival

Visualizing the Effect of
Mutations on Patient Risk

Visualizing the Effect of Mutations on Patient Risk

Using the IPSS-M Risk Calculator

The most recent version of the International Prognostic Scoring System, the IPSS-M, incorporates molecular gene mutations (such as IDH1 and IDH2) to improve risk stratification and therapeutic decision-making in MDS.14,15

The addition of molecular mutations to a baseline profile may “upstage” an MDS patient into a higher risk category.15

The most recent version of the International Prognostic Scoring System, the IPSS-M, incorporates molecular gene mutations (such as IDH1 and IDH2) to improve risk stratification and therapeutic decision-making in MDS.14,15

The addition of molecular mutations to a baseline profile may “upstage” an MDS patient into a higher risk category.15

Image: IPSS-M Risk Calculator - Patient No Mutations
Image: IPSS-M Risk Calculator - Patient +mIDH1
Image: IPSS-M Risk Calculator - Patient +mIDH2

The Importance of Expedited
Mutational Testing

Molecular profiling is part of the standard workup for AML and highly recommended in MDS. 19,20

Due to the negative prognostic impact of certain mutations, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend expedited testing at diagnosis, and repeated testing at relapse and progression.20

A large, real-world data analysis has proven that a short delay for mutational testing has no negative bearing on outcomes in AML.21

Molecular profiling is part of the standard workup for AML and highly recommended in MDS. 19,20

Due to the negative prognostic impact of certain mutations, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend expedited testing at diagnosis, and repeated testing at relapse and progression.20

A large, real-world data analysis has proven that a short delay for mutational testing has no negative bearing on outcomes in AML.21

Find a Test Center (Coming Soon)

Recent advances in mutational testing techniques and availability at commercial reference laboratories have improved turnaround times to as few as 3-5 days.22–24

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References:

1.  Pirozzi CJ and Yan H. Nat Rev Clin Oncol. 2021;18(10):645-661. doi:10.1038/s41571-021-00521-0
2. Phillips C. National Cancer Institute Website. https://www.cancer.gov/news-events/cancer-currents-blog/2022/idh1-cancer-metabolite-blocks-immune-cells. Accessed May 12, 2023. 3. RCSB Protein Data Bank website. https://doi.org/10.2210/pdb3MAP/pdb Accessed May 18, 2023. 4. Lu C, et al. Nature. 2012;483(7390):474-478. doi:10.1038/nature10860 5. Chowdhury R, et al. EMBO Rep. 2011;12(5):463-469. doi:10.1038/embor.2011.43 6. Wu N, et al. Biomol Ther. 2016;24(1):1-8. doi:10.4062/biomolther.2015.078 7. Losman JA and Kaelin WG. Genes Dev. 2013;27(8):836-852. doi:10.1101/gad.217406.113 8. Cairns RA and Mak TW. Cancer Discov. 2013;3(7):730-741. doi:10.1158/2159-8290.CD-13-0083 9. Medeiros BC,. Leukemia. 2017;31(2):272-281. doi:10.1038/leu.2016.275 10. Jin J, et al. PLoS ONE. 2014;9(6):e100206. doi:10.1371/journal.pone.0100206 11. Thol F, et al. Haematologica. 2010;95(10):1668-1674. doi:10.3324/haematol.2010.025494 12. DiNardo CD, et al. Leukemia. 2016;30(4):980-984. doi:10.1038/leu.2015.211 13. UpToDate® website. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-myelodysplastic-syndromes-mds. Accessed February 24, 2023. 14. IPSS-M Risk Calculator website. https://mds-risk-model.com/. Accessed March 25, 2023. 15. Bernard E, et al. NEJM Evid. 2022;1(7)1-14. doi:10.1056/EVIDoa2200008 16. Aguirre LE, et al. Leukemia. Published online May 5, 2023. doi:10.1038/s41375-023-01910-3 17. Cazzola M. Hematology. 2022; (1):375-381. doi:10.1182/hematology.2022000349 18. Abbas S, et al. Blood. 2010;116(12):2122-2126. doi:10.1182/blood-2009-11-250878 19. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myelodysplastic Syndromes V.1.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed April 24, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org 20. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.3.2023. © National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed April 24, 2023. To view the most recent and complete version of the guideline, go online to NCCN.org 21. Röllig C, et al. Blood. 2020;136(7):823-830. doi:10.1182/blood.2019004583 22. Neogenomics Website. https://neogenomics.com/test-menu/idh1. Accessed March 23,2023. 23. Labcorp.com website. https://www.labcorp.com/tests/481484/i-idh1-idh2-i-mutation-analysis. Accessed March 23,2023. 24. Questdiagnostics.com website. https://testdirectory.questdiagnostics.com/test/test-detail/31547/isocitrate-dehydrogenase-1-and-2-idh1idh2-mutation-analysis?cc=MASTER. Accessed March 23,2023.

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