User:Mbanting/sandbox

NOTE
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
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. The mutations occur at conserved arginine residues, the most frequent being the R132H mutation in which arginine is replaced by a histidine residue. 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. D2-HG inhibits the function of many alpha-ketoglutarate dependent enzymes, including histone and DNA demethylases that remove methyl groups from histones and DNA. This causes widespread changes in histone and DNA methylation and may promote tumor formation. 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. This phenotype is common in certain cancers and can cause changes in gene expression, such as gene silencing. The IDH1 mutation is believed to promote the formation of this phenotype. 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.

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

IDH1 and Cancer
The R132H missense mutation involves the substitution of guanine for adenine and is present in 90% of cancers containing IDH1 mutations. This mutation is more commonly found in secondary glioblastomas and high grade oligodendrogliomas, and appears early in glioma development. Mutations in IDH1 have also been reported in acute myeloid leukemia, cholangiocarcinoma, melanomas and cartilaginous tumors. 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.

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. This was supported by evidence of histone hypermethylation and/or increased levels of D2-HG in cell lines following IDH1 mutant expression.

Potential for Targeted Diagnosis and Therapy
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. Mutant-specific antibodies have proven some use in immunohistochemical screens for the mutant enzyme. As the mutation occurs early in glioma development, this marker allows for earlier diagnosis. As well, identification of IDH1 mutant tumors may provide accurate diagnostic and prognostic information.


 * 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. 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.
 * Small molecule inhibitors are a potential future therapeutic for individuals with IDH1 mutant-expressing tumors. Competitive inhibitors specific to the mutant enzyme are currently in clinical trials. They act by binding the active site of the mutant IDH1 enzyme and prevent binding of the substrate alpha-ketoglutarate. This prevents the enzyme from forming D2-HG and leads to a reduction in D2-HG levels.