User:Mbanting/sandbox
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NOTE
[edit]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
[edit]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 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
[edit]IDH1 and Cancer
[edit]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
[edit]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]
- Targeted Therapy
- The occurrence of site specific mutations, along with ubiquitous expression through all tumor cells, allows for targeting of mutant-expressing cells by vaccine-based immunotherapy.[4] This strategy uses a vaccine to induce the immune system to recognize and destroy target cells, though currently none have been developed that specifically target the mutant R132H enzyme.[4][3]
- Small molecule inhibitors are a potential future therapeutic for individuals with IDH1 mutant-expressing tumors.[4] Competitive inhibitors specific to the mutant enzyme are currently in clinical trials.[4] They act by binding the active site of the mutant IDH1 enzyme and prevent binding of the substrate alpha-ketoglutarate.[4] This prevents the enzyme from forming D2-HG and leads to a reduction in D2-HG levels.[4]
References
[edit]- ^ 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) - ^ 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) - ^ 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.
- ^ 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) - ^ 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.