A systematic review of high impact CpG sites and regions for MGMT methylation in glioblastoma [A systematic review of MGMT methylation in GBM].

BACKGROUND: MGMT (O 6 -methylguanine-DNA methyltransferase) promoter methylation is a commonly assessed prognostic marker in glioblastoma (GBM). Epigenetic silencing of the MGMT gene by promoter methylation is associated with greater overall and progression free survival with alkylating agent regimens. To date, there is marked heterogeneity in how MGMT promoter methylation is tested and which CpG sites are interrogated. METHODS: To further elucidate which MGMT promoter CpG sites are of greatest interest, we performed comprehensive searches in PubMed, Web of Science, and Embase and reviewed 2,925 article abstracts. We followed the GRADE scoring system to assess risk of bias and the quality of the studies we included. RESULTS: We included articles on adult glioblastoma that examined significant sites or regions within MGMT promoter for the outcomes: overall survival, progression free survival, and/or MGMT expression. We excluded systemic reviews and articles on lower grade glioma. fifteen articles met inclusion criteria with variable overlap in laboratory and statistical methods employed, as well as CpG sites interrogated. Pyrosequencing or BeadChip arrays were the most popular methods utilized, and CpG sites between CpG's 70-90 were most frequently investigated. Overall, there was moderate concordance between the CpG sites that the studies reported to be highly predictive of prognosis. Combinations or means of sites between CpG's 73-89 were associated with improved OS and PFS. Six studies identified CpG sites associated with prognosis that were closer to the transcription start site: CpG's 8, 19, 22, 25, 27, 32,38, and CpG sites 21-37, as well as low methylation level of the enhancer regions. CONCLUSION: The following systematic review details a comprehensive investigation of the current literature and highlights several potential key CpG sites that demonstrate significant association with OS, PFS, and MGMT expression. However, the relationship between extent of MGMT promoter methylation and survival may be non-linear and could be influenced by potential CpG hotspots, the extent of methylation at each CpG site, and MGMT enhancer methylation status. There were several limitations within the studies such as smaller sample sizes, variance between methylation testing methods, and differences in the various statistical methods to test for association to outcome. Further studies of high impact CpG sites in MGMT methylation is warranted.

Reductive carboxylation is a major metabolic pathway in the retinal pigment epithelium.

The retinal pigment epithelium (RPE) is a monolayer of pigmented cells that requires an active metabolism to maintain outer retinal homeostasis and compensate for oxidative stress. Using 13C metabolic flux analysis in human RPE cells, we found that RPE has an exceptionally high capacity for reductive carboxylation, a metabolic pathway that has recently garnered significant interest because of its role in cancer cell survival. The capacity for reductive carboxylation in RPE exceeds that of all other cells tested, including retina, neural tissue, glial cells, and a cancer cell line. Loss of reductive carboxylation disrupts redox balance and increases RPE sensitivity to oxidative damage, suggesting that deficiencies of reductive carboxylation may contribute to RPE cell death. Supporting reductive carboxylation by supplementation with an NAD+ precursor or its substrate α-ketoglutarate or treatment with a poly(ADP ribose) polymerase inhibitor protects reductive carboxylation and RPE viability from excessive oxidative stress. The ability of these treatments to rescue RPE could be the basis for an effective strategy to treat blinding diseases caused by RPE dysfunction.

The IDH1 inhibitor ivosidenib improved seizures in a patient with drug-resistant epilepsy from IDH1 mutant oligodendroglioma.

Compared to high grade gliomas, low grade gliomas such as oligodendrogliomas are often more epileptogenic. Epilepsy develops in 70-90% of patients with oligodendrogliomas and 40% of these are resistant to anti-seizure medications and surgery [3]. IDH1/2 mutation is one defining feature of oligodendrogliomas and confers improved prognosis when found in astrocytomas [7]. One possible etiology of the high rate of epileptogenicity in oligodendrogliomas is D-2-Hydroxyglutarate (D2HG), an oncometabolite seen in IDH mutation [8]. D2HG can mimic the effect of glutamate at the NMDA receptor and increase the seizure risk [11]. In this case report, we present a patient with drug resistant focal epilepsy from IDH1 mutant oligodendroglioma with markedly improved seizure frequency after starting Ivosidenib, an IDH1 inhibitor, in the absence of any changes to traditional anti-seizure medications. Our case suggests the possibility that IDH1 inhibitors may help reduce seizure burden in patients with difficult to control epilepsy from IDH1 mutant oligodendrogliomas. This is significant because we show that a targeted cancer therapy is able to improve seizure frequency through a unique pathway, and suggests that research into similar targeted, precision medicine therapies in brain lesions associated with epilepsy may be beneficial.