IDH1 gene mutation [Neurosurgery Wiki]

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====== IDH1 gene mutation ======


IDH1 [[gene mutation]]s refer to genetic alterations that occur in the isocitrate dehydrogenase 1 (IDH1) gene. The IDH1 gene encodes the enzyme [[isocitrate dehydrogenase 1]], which is involved in cellular metabolism and the citric acid cycle.

Mutations in the IDH1 gene are most commonly observed in certain types of cancer, particularly gliomas (brain tumors) and acute myeloid leukemia (AML). The most prevalent mutation in the IDH1 gene is a substitution of arginine (R) with histidine (H) at position 132 (IDH1-R132H). This mutation leads to a change in the structure and function of the IDH1 enzyme.

The IDH1-R132H mutation confers a gain-of-function property to the mutated IDH1 enzyme. Instead of catalyzing the normal conversion of isocitrate to alpha-ketoglutarate (a key intermediate in cellular metabolism), the mutant IDH1 enzyme catalyzes a different reaction. It converts alpha-ketoglutarate into an abnormal metabolite called D-2-hydroxyglutarate (D-2-HG). This results in the accumulation of D-2-HG in cells, which disrupts normal cellular processes and contributes to tumorigenesis.

The presence of IDH1 mutations, particularly the IDH1-R132H mutation, has diagnostic and prognostic implications in certain cancers. It can be detected through genetic testing or molecular diagnostics, and its presence in tumor cells can help in the classification and management of specific cancers. Additionally, targeted therapies are being developed to specifically inhibit the mutant IDH1 enzyme and reduce the levels of D-2-HG as a potential treatment strategy for IDH1-mutant cancers.

It's important to note that IDH1 mutations are specific to the IDH1 gene and should not be confused with mutations in the IDH2 gene, which is a closely related gene that also encodes an isocitrate dehydrogenase enzyme (IDH2).

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● [[IDH-wildtype]] is a normal enzyme in the [[Krebs cycle]], catalyzing [[isocitrate]] → [[α-ketoglutarate]]

● mutant IDH occurs in many [[tumor]]s, but not in normal cells. [[IDH1]] is the most common [[mutation]].

One metabolite is [[alpha-Hydroxyglutaric acid]] which may participate in [[tumorigenesis]]

● [[IDH mutation]]s are found in 70–80% of secondary GBMs and their precursors (grade II & grade III gliomas), but in only 5% of primary GBMs

● prognosis in tumors with mutated IDH is better than those with [[IDH-wildtype]]

● WHO recommends testing for [[IDH mutation]]s in all [[astrocytic tumor]]s.




see [[IDH-mutant glioma]].
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Isocitrate dehydrogenase ([[IDH1]]) gene is the most prominent [[molecular marker]] of glioma prognosis, response to therapy, and patient survival. There are conflicting data about the effect of IDH1 mutation on [[glial cell]] [[proliferation]], invasion, and migration characteristics. results highlighted that IDH1 mutation upregulates the [[mTOR]] [[signaling pathway]] and promote cell proliferation, invasion, and migration.
((Avsar T, Kose TB, Oksal MD, Turan G, Kilic T. IDH1 mutation activates mTOR signaling pathway, promotes cell proliferation and invasion in glioma cells. Mol Biol Rep. 2022 Aug 7. doi: 10.1007/s11033-022-07750-1. Epub ahead of print. PMID: 35934766.))
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The combination of [[P53]] and [[IDH1]] as an immunohistochemical panel showed a specificity of 96% and [[sensitivity]] of 91% for [[differential diagnosis]] of [[reactive gliosis]] and [[low-grade astrocytoma]]. These 2 markers can be extremely helpful for this differential diagnosis
((Geramizadeh B, Kohandel-Shirazi M, Soltani A. A Simple Panel of IDH1 and P53 in Differential Diagnosis Between Low-Grade Astrocytoma and Reactive Gliosis. Clin Pathol. 2021 Feb 11;14:2632010X20986168. doi: 10.1177/2632010X20986168. PMID: 33634261; PMCID: PMC7887675.)).
----


[[IDH1]] Arg132 mutations and [[IDH2]] Arg140 and Arg172 mutations accounting for >90% of aberrations
((Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl JMed. 2009; 360:765–773))
((Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321:1807–1812)).
IDH1 and IDH2 mutations reduce the enzymatic capacity of these proteins to bind [[isocitrate]], their substrate, and convert it into [[alpha-ketoglutaric acid]] (α-KG), generating [[carbon dioxide]] and replenishing [[NADH]] and [[NADPH]] as side products
((Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene. 2010; 29:6409– 6417)).
This is one of the irreversible steps in the [[tricarboxylic acid]] cycle important for cellular respiration. Mutant IDH1 (cytoplasmic) and IDH2 (mitochondrial) enzymes also show a modified enzymatic capacity to convert α-KG into 2- hydroxyglutarate (2-HG), a small [[oncometabolite]]. Equally important, IDH1 and IDH2 mutations stratify individuals into molecular subtypes with distinct clinical outcomes – the mutations are associated with lower-grade [[astrocytoma]]s, [[oligodendroglioma]]s (grade II/III) and secondary gliomas with better [[overall survival]], [[progression-free survival]] and [[chemosensitivity]] than [[glioblastoma]]s that are [[wild type]] for both genes
((Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl JMed. 2009; 360:765–773))
((Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321:1807–1812))
((Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene. 2010; 29:6409– 6417)).
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Data support an evolutionary model in which [[IDH mutation]] glioma cells exist in [[symbiosis]] with supportive neuronal cells and [[astrocyte]]s as suppliers of [[glutamate]] and [[lactate]], possibly explaining the diffuse nature of these cancers. The dependency on glutamate and lactate opens the way for novel approaches in the treatment of IDHmut gliomas
((Lenting K, Khurshed M, Peeters TH, van den Heuvel CNAM, van Lith SAM, de
Bitter T, Hendriks W, Span PN, Molenaar RJ, Botman D, Verrijp K, Heerschap A, Ter
Laan M, Kusters B, van Ewijk A, Huynen MA, van Noorden CJF, Leenders WPJ.
Isocitrate dehydrogenase 1-mutated human gliomas depend on lactate and glutamate 
to alleviate metabolic stress. FASEB J. 2018 Jul 12:fj201800907RR. doi:
10.1096/fj.201800907RR. [Epub ahead of print] PubMed PMID: 30001166.
)).

IDH1 mutation is important for prognosis of [[glioma]]s and represents a distinctive category of glioma.

Increased [[overall survival]] for patients with [[glioma]] is associated with [[mutation]]s in the metabolic regulator [[isocitrate dehydrogenase 1]] (IDH1).

Acquisition of IDH1 or [[IDH2]] mutation (IDHmut) is among the earliest genetic events that take place in the development of most [[Low-grade glioma]] (LGG). IDHmut has been associated with longer overall patient survival. However, its impact on malignant transformation (MT) remains to be defined. 

Studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of Glioblastomas
((Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter 
H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T,
Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL,
Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N,
Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic
analysis of human glioblastoma multiforme. Science. 2008 Sep
26;321(5897):1807-12. doi: 10.1126/science.1164382. Epub 2008 Sep 4. PubMed PMID:
18772396; PubMed Central PMCID: PMC2820389.)).

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Mutations in the [[IDH1]] and IDH2 genes encoding isocitrate dehydrogenases suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary [[glioblastoma]]s
((Chen R, Ravindra VM, Cohen AL, Jensen RL, Salzman KL, Prescot AP, Colman H.
Molecular features assisting in diagnosis, surgery, and treatment decision making
in low-grade gliomas. Neurosurg Focus. 2015 Mar;38(3):E2. doi:
10.3171/2015.1.FOCUS14745. PubMed PMID: 25727224.)).

A study confirms that long-term survival in Glioblastoma patients is if at all only weakly correlated to IDH-mutation
((Amelot A, De Cremoux P, Quillien V, Polivka M, Adle-Biassette H, Lehmann-Che
J, Françoise L, Carpentier AF, George B, Mandonnet E, Froelich S. IDH-Mutation Is
a Weak Predictor of Long-Term Survival in Glioblastoma Patients. PLoS One. 2015
Jul 9;10(7):e0130596. doi: 10.1371/journal.pone.0130596. eCollection 2015. PubMed
PMID: 26158269; PubMed Central PMCID: PMC4497660.)).
----
Miroshnikova et al., found that [[glioma]] aggression and patient prognosis correlate with [[HIF1A]] levels and the stiffness of a tenascin C (TNC)-enriched ECM. Gain- and loss-of-function xenograft manipulations demonstrated that a mutant [[IDH1]] restricts glioma aggression by reducing HIF1α-dependent TNC expression to decrease ECM stiffness and mechanosignalling. Recurrent IDH1-mutant patient gliomas had a stiffer TNC-enriched ECM that the studies attributed to reduced miR-203 suppression of HIF1α and TNC mediated via a tension-dependent positive feedback loop. The work suggests that elevated ECM stiffness can independently foster glioblastoma aggression and contribute to glioblastoma recurrence via bypassing the protective activity of IDH1 mutational status
((Miroshnikova YA, Mouw JK, Barnes JM, Pickup MW, Lakins JN, Kim Y, Lobo K,
Persson AI, Reis GF, McKnight TR, Holland EC, Phillips JJ, Weaver VM. Tissue
mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate
glioblastoma aggression. Nat Cell Biol. 2016 Nov 7. doi: 10.1038/ncb3429. [Epub
ahead of print] PubMed PMID: 27820599.
)).

====Analysis====
Conventional methods for isocitrate dehydrogenase 1 (IDH1) detection, such as DNA sequencing and immunohistochemistry, are time- and labor-consuming and cannot be applied for intraoperative analysis. To develop a new approach for rapid analysis of IDH1 mutation from tiny tumor samples, a study used microfluidics as a method for IDH1 mutation detection. 

Forty-seven glioma tumor samples were used; IDH1 mutation status was investigated by immunohistochemistry and DNA sequencing. The microfluidic device was fabricated from polydimethylsiloxane following standard soft lithography. The immunoanalysis was conducted in the microfluidic chip. Fluorescence images of the on-chip microcolumn taken by the charge-coupled device camera were collected as the analytical results readout. Fluorescence signals were analyzed by NIS-Elements software to gather detailed information about the IDH1 concentration in the tissue samples. 

DNA sequencing identified IDH1 R132H mutation in 33 of 47 tumor samples. The fluorescence signal for IDH1-mutant samples was 5.49 ± 1.87 compared with 3.90 ± 1.33 for wild type (p = 0.005). Thus, microfluidics was capable of distinguishing IDH1-mutant tumor samples from wild-type samples. When the cutoff value was 4.11, the sensitivity of microfluidics was 87.9% and the specificity was 64.3%. 

This new approach was capable of analyzing IDH1 mutation status of tiny tissue samples within 30 minutes using intraoperative microsampling. This approach might also be applied for rapid pathological diagnosis of diffuse gliomas, thus guiding personalized resection
((Aibaidula A, Zhao W, Wu JS, Chen H, Shi ZF, Zheng LL, Mao Y, Zhou LF, Sui GD. 
Microfluidics for rapid detection of isocitrate dehydrogenase 1 mutation for
intraoperative application. J Neurosurg. 2016 Jun;124(6):1611-8. doi:
10.3171/2015.4.JNS141833. Epub 2015 Nov 6. PubMed PMID: 26544771.
)).