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Emerging Biomedical Analysis
Published in Lawrence S. Chan, William C. Tang, Engineering-Medicine, 2019
As one can see, one of the key elements allowing for the development of this diagnostic method was the discovery of a tumor-specific metabolite. A recent finding revealed that there was a mutation of the isocitrate dehydrogenase-1 (IDH1) gene present in a large majority of the common brain tumor glioma, with elevated levels up to 100-fold compared to wild type IDH1. This mutation and resulting gain-of-function leads to the production of the tumor-specific metabolite, 2-hydroxyglutarate (2-HG), which is not present in normal tissue. Besides glioma, the IDH1 mutation is also found in acute myeloid leukemia, cholangiocarcinoma, chondrosarcoma, and T cell lymphoma. These findings gave a substantial advantage for the development of tumor margin detection using MS (Pope 2014). Alternatively, other chemicals, if substantially different in quantity between tumor and normal tissues, can also be used for this identification purpose.
Precision medicine for brain gliomas
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Different than classical glioblastomas, TP53 is significantly mutated in proneural glioblastomas (54%). These glioblastomas are also characterized by having the most frequent mutations in the IDH1 gene. IDH1, when mutated, codes for a protein that can contribute to abnormal cell growth (Verhaak et al., 2010). Another gene, platelet derived growth factor receptor alpha (PDGFRA), was mutated and expressed in abnormally high amounts only in the proneural glioblastomas and not in any other subgroups. When PDGFRA is altered, too much of its protein can be produced, leading to uncontrolled tumor growth (Müller et al., 2016). Unlike the other groups, whose patients were similar in age on average, the proneural subgroup was significantly younger. They also tended to survive longer. However, patients in the proneural group who received aggressive treatment did not survive significantly longer than proneural patients who did not receive aggressive treatment. This is important for precision medicine in glioblastoma and clinicians may be able to use this information in the future to avoid unnecessary treatment regimens for patients in the proneural glioblastomas (Verma et al., 2016).
Central nervous system
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Anthony Chalmers, Allan James, Roy Rampling
Co-deletion of 1p19q is observed in approximately 70% of anaplastic oligodendrogliomas (AOs) and 30% of anaplastic oligoastrocytomas (AOAs) and is associated with good prognosis. In the landmark RTOG 9402 study of radiotherapy +/- chemotherapy for AOs and AOAs, median survival for patients with 1p19q co-deletion receiving radio- and chemotherapy was nearly 15 years, compared with only 2.5 years for patients without co-deletion.9 Addition of PCV chemotherapy (see the section ‘Combination Chemotherapy’) to radiotherapy doubled the median survival for co-deleted patients but did not improve outcomes for patients without 1p19q co-deletion. LOH 1p19q can also be detected in up to 15% of anaplastic astrocytomas (AAs), and in these cases the favourable molecular marker may outweigh the unfavourable histological subtype. IDH1 mutation is observed in about 60% of anaplastic gliomas and is a positive prognostic marker, but it does not appear to be a useful independent predictor of chemosensitivity. Nonetheless, IDH1 mutation correlates very strongly with hypermethylation of the MGMT gene promoter in anaplastic gliomas.
HLA-G 5′URR regulatory polymorphisms are associated with the risk of developing gliomas
Published in International Journal of Neuroscience, 2023
Vladimira Durmanova, Kristina Kluckova, Barbora Filova, Gabriel Minarik, Jan Kozak, Boris Rychly, Marian Svajdler, Viktor Matejcik, Juraj Steno, Maria Bucova
Detailed parameters of the 59 enrolled patients with gliomas are summarized in Table 1. The average age at disease onset was 53.36 ± 15.17 years. According to histopathological characteristics, the 18 patients have been classified grade II tumors (oligodendroglioma, astrocytoma), 12 patients grade III tumors (anaplastic astrocytoma, anaplastic oligodendroglioma) and 29 patients grade IV tumors (glioblastoma multiforme). The time of overall survival (OS) ranged from 0 months to 39.5 months with an average survival of 28.03 ± 12.22 months for grade II, 19.09 ± 11.88 for grade III and 9.98 ± 8.35 for grade IV. The progression-free survival ranged from 0 months to 35 months with an average survival of 12.72 ± 10.12 months. IDH1/2 mutations were present in 22 patients with grade II and III gliomas, and in no patient with grade IV gliomas.
An evaluation of ivosidenib for the treatment of IDH1-mutant cholangiocarcinoma
Published in Expert Opinion on Pharmacotherapy, 2022
Sri Harsha Tella, Amit Mahipal
Isocitrate dehydrogenase (IDH) enzyme is a key metabolic enzyme in tricarboxylic acid (Krebs) cycle located in cytoplasm and mitochondrial matrix. IDH1 is predominantly located in cytoplasm, whereas mitochondria harbors IDH2 and IDH3 subtypes. In unaltered cellular physiology, IDH enzymes catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in Krebs cycles. Mutations in IDH1 and IDH2 genes have been identified in several malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome and myeloproliferative neoplasms, glioblastomas, chondrosarcomas, thyroid malignancies, and cholangiocarcinoma. These mutated IDH enzymes acquire gain-of-function activity, converting αKG to the oncometabolite D-2-hydroxyglutarate (2-HG) [30]. Elevated 2-HG levels interfere with cellular metabolism, augment reactive oxygen species, induce hypoxia-inducible factor, and modify epigenetic regulation by causing hypermethylation of DNA and histones, thereby contributing to oncogenesis (Figure 1) [30]. Patients with cholangiocarcinoma harboring IDH1 mutation may have a prolonged clinical course compared to patients without IDH mutations [31].
Combinatorial approaches to effective therapy in glioblastoma (GBM): Current status and what the future holds
Published in International Reviews of Immunology, 2022
Sweety Asija, Abhishek Chatterjee, Sandhya Yadav, Godhanjali Chekuri, Atharva Karulkar, Ankesh Kumar Jaiswal, Jayant S. Goda, Rahul Purwar
In LGG, a hallmark metabolite is the oncometabolite 2-hydroxyglutarate (2-HG) is produced as a byproduct in abundance by R132H mutant IDH1 using α-ketoglutarate as a substrate [61]. 2-HG mediated response is involved in the phenotypic and epigenetic regulations of glioma cells. Thus, mutant IDH1 directly plays a vital role in remodeling the TME by inducing the glioma CpG island methylator phenotype (G-CIMP) which is known as a relevant positive prognostic marker for glioma and GBM [61,62]. Recently the focus has shifted toward the role of wild-type IDH1 in GBM, overexpression of wild-type IDH1 (present in the cytosol) is an important regulator of tumor progression and is mostly found in primary GBM. IDH1 is an NADPH synthesizing enzyme that is differentially expressed [63]. Fatty acid synthesis and activation of reactive oxygen species scavenging via IDH1 causes tumor progression and resistance therapy. [64]. Wild-type IDH2 and IDH3 are present in mitochondria where IDH3 converts isocitrate back to α ketoglutarate (αKG). Due to the structural similarity between αKG and 2-HG, 2-HG inhibits αKG-dependent dioxygenases function thereby resulting in epigenetic changes, alterations in cellular differentiation status and hypoxia inducible factor-1 (HIF-1) stabilization, a factor that paves a ways for hypoxia driven angiogenesis [65].