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idh1

Isocitrate dehydrogenase‑1 (IDH1)

Increased overall survival for patients with glioma is associated with mutations 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 GBMs 1).


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 glioblastomas 2).

A study confirms that long-term survival in GBM patients is if at all only weakly correlated to IDH-mutation 3).


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 4).

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 5).

1)
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.
2)
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.
3)
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.
4)
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.
5)
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.
idh1.txt · Last modified: 2016/11/08 11:33 (external edit)