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NOTE

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Some sentences, particularly in the Clinical Relevance section, may come off as original research. However, all of this information comes from review papers and evidence or techniques I have mentioned have been reproduced many times and are well accepted in this area of research.

Mutation

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Mutations of the IDH1 enzyme are typically heterozygous, involving an amino acid substitution in the active site of the enzyme where isocitrate binds to undergo oxidative decarboxylation.[1][2] The mutations occur at conserved arginine residues, the most frequent being the R132H mutation in which arginine is replaced by a histidine residue.[3]

The molecular structure of the IDH1 enzyme, both wild type and mutant. Magnified cutaway depicts the R132H mutation that is prevalent in gliomas.

The mutation results in a loss of normal enzymatic function and the abnormal production of D2-hydroxyglutarate (D2-HG), consuming the substrates NADPH and alpha-ketoglutarate in the process.[1][3] D2-HG inhibits the function of many alpha-ketoglutarate dependent enzymes, including histone and DNA demethylases that remove methyl groups from histones and DNA.[2] This causes widespread changes in histone and DNA methylation and may promote tumor formation.[2] For example, IDH1 mutations are correlated with the CpG island methylator phenotype where there is an increase in methylation of cytosine nucleotides that fall next to guanine nucleotides.[3] This phenotype is common in certain cancers and can cause changes in gene expression, such as gene silencing.[4] The IDH1 mutation is believed to promote the formation of this phenotype.[3][4] Similarly, mutations of arginine residues in the active site of the isocitrate dehydrogenase isoform IDH2 lead to the production D2-HG and are linked to hypermethylation in cancers.[2]

Due to the presence of a wild type allele, heterodimers form consisting of a mutant and wild type subunit.[1] The wild type subunit is deemed necessary for efficient production of D2-HG, suggesting a need for heterozygosity.[1][4]

Clinical Relevance

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IDH1 and Cancer

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The R132H missense mutation involves the substitution of guanine for adenine and is present in 90% of cancers containing IDH1 mutations.[4] This mutation is more commonly found in secondary glioblastomas and high grade oligodendrogliomas, and appears early in glioma development.[4] Mutations in IDH1 have also been reported in acute myeloid leukemia, cholangiocarcinoma, melanomas and cartilaginous tumors.[3] These mutations are found more commonly in younger patients and are associated with positive outcomes or prolonged survival compared to similar cancers containing wild type IDH1.[4]

Due to the presumed oncogenic and epigenetic role of D2-HG, an accepted model theorizes that the main cancer promoting role of IDH mutations is to alter DNA and histone methylation, thereby altering normal cellular differentiation processes.[3] This was supported by evidence of histone hypermethylation and/or increased levels of D2-HG in cell lines following IDH1 mutant expression.[4]

Potential for Targeted Diagnosis and Therapy

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The R132H mutation has been targeted in the design of mutant-specific therapies and diagnostic tests, such as:

  • Biomarker Function
    • Due to its high prevalence in glioma and secondary glioblastoma, the R132H mutation was tested for use as a biomarker to detect cancer cells expressing the mutant enzyme.[2] Mutant-specific antibodies have proven some use in immunohistochemical screens for the mutant enzyme.[5] As the mutation occurs early in glioma development, this marker allows for earlier diagnosis.[2] As well, identification of IDH1 mutant tumors may provide accurate diagnostic and prognostic information.[3]

References

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  1. ^ a b c d Das, Sunit; Karamchandani, Jason (2014). "IDH mutation in glioma". JAMA Neurology. 71 (10): 1319-1325. {{cite journal}}: |access-date= requires |url= (help)
  2. ^ a b c d e f Ling, Zhi-Qiang; Liu, Xiang (2015). "Role of isocitrate dehydrogenase 1/2 (IDH 1/2) gene mutations in human tumors". Histology Histopathology. 30: 1155–1160. {{cite journal}}: |access-date= requires |url= (help)
  3. ^ a b c d e f g h Waitkus, Matthew S.; Diplas, Bill H.; Yan, Hai (2015). "Isocitrate dehydrogenase mutations in gliomas". Neuro-Oncology. 0: 1–11. doi:10.1093/neuonc/nov136.
  4. ^ a b c d e f g h i j k l m Dimitroc, Lilia; Hong, Christopher S.; Yang, Chunzhang; Zhuang, Zhengping; Heiss, John D. (2015). "New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma". International Journal of Medical Sciences. 12 (3): 201–213. {{cite journal}}: |access-date= requires |url= (help)
  5. ^ Horbinski, Craig (2013). "What do we know about IDH1/2 mutations so far, and how do we use it?". Acta Neuropathologica. 125 (5): 621–636. doi:10.1007/s00401-013-1106-9.