Background - Molecular profiles can predict which patients will respond to current standard treatment and new targeted therapy regimens. Using data from a highly diverse population of approximately three million in Southeast London and Kent, this study aims to evaluate the prevalence of IDH1 mutation and MGMT promotor methylation in the gliomas diagnosed in adult patients and to explore correlations with patients’ clinicopathological characteristics. Methods - Anonymised data on 749 adult patients diagnosed with a glioma in 2015-2019 at King’s College Hospital were extracted. Univariable and multivariable logistic regressions were used to estimate odds ratios (ORs) for expressing IDH1 mutation and MGMT promotor methylation, based on each patient’s age, sex, ethnicity, histology, tumour location and extent of excision. The Kaplan-Meier method was used to estimate the overall survival functions. Results - 19.5% of cases were IDH1 mutated. Being 39 years and younger (OR 5.48, 95% CI 3.17-9.47), from Asian/Asian British background (OR 3.68, 95% CI 1.05-12.97), having MGMT methylation (OR 15.92, 95% CI 7.30-34.75), an oligodendroglioma diagnosis (OR 7.45, 95% CI 2.90-19.13) and receiving a gross total/total microscopic excision (OR 1.95, 95% CI 1.24-3.08) were each univariately correlated with IDH1 mutation. MGMT methylation association persisted on adjustment (OR 14.13, 95% CI 3.88-51.43). MGMT promotor methylation was seen in 54.3 % of gliomas. In the univariate adjusted ORs, being younger than 39 years (OR 2.56, 95% CI 1.48-4.43), female (OR 1.52, 95% CI 1.11-2.08), having IDH1 mutation (OR 15.92, 95% CI 7.30-34.75) and an oligodendroglioma diagnosis (OR 6.20, 95% CI 1.33-28.88) were associated with MGMT methylation. Being female (OR 1.75, 95% CI 1.22-2.51) and having an IDH1 mutation (OR 15.54, 95% CI 4.73-51.05) persisted after adjustment for age, sex, ethnicity, histology, tumour location and extent of excision. IDH1 mutant and MGMT methylated gliomas were associated with frontal lobe location. Survival analysis showed that patients with both IDH1 mutation and MGMT methylation had a significantly better survival than those with either molecular marker alone. Over a 3-year period, women with unmethylated MGMT promotor generally had a better survival than men with unmethylated MGMT. Conclusion - This study showed that the molecular markers IDH1 mutation and MGMT promotor methylation were associated with age, sex, Asian/Asian British Ethnic Group, tumour histology, anatomical location and extent of excision. This study has demonstrated the importance of assessing glioma molecular markers in the clinical setting, and the need to stratify patients according to their clinicopathological characteristics.

How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we studied isocitrate dehydrogenases (IDH) genes mutations in the human model of HSPC and provide a review of the literature on this topic. IDH1/2 mutations occur in ~20% of AML, are recognized among the mutations earliest acquired during leukemogenesis, and are target of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on the HSPC we expressed by lentiviral transduction either IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by the specific inhibitors, confirming it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed over time a progressive and marked improvement of their fitness in terms of CFU ability and propensity to differentiate, attaining clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

Glioblastoma is a solid, infiltrating and the most frequent highly malignant primary brain tumor. Our aim was to find the prognostic value of mutations of IDH1, MGMT, EGFR, p53, ATRX, Ki67 genes and the correlation between sex, age, presenting with seizures, number of interventions, extent of resection with Overall Survival (OS), Progression Free Survival (PFS) and Karnofsky performance status (KPS) score. A randomized retrospective analysis of 122 patients treated by a single operator at Sapienza University of Rome, was carried out. After surgery patients followed standard treatment Stupp protocol [6]. Exclusion criteria were: patients with primitive brainstem and spinal cord gliomas and patients who underwent partial resections (resection < 90%) and cases of brain biopsy exclusively for diagnostic purposes. Statistical analysis with a simultaneous regression model was carried on by SPSS 25 ® (IBM) program. Results showed statistically significant survival increase in four groups: 1) patients treated with gross total resection (p< 0.03); 2) patients with methylated MGMT promoter (p<0.005); 3) patients with non EGFR amplification or EGFRvIII mutation (p<0.035); 4) mutated IDH1/IDH2 (p<0.0161). Higher survival rates (but not statistically significant) were observed also in patients with: age < 75 years, Ki 67 <10%, lesions in non eloquent areas, ATRX gene mutation and presentation with seizures.

In 2021, the World Health Organization classified isocitrate dehydrogenase (IDH) mutant gliomas as a distinct subgroup of tumors with genetic changes sufficient to enable a complete diagnosis. Patients with an IDH mutant glioma have improved survival which has been further enhanced by the advent of targeted therapies. IDH enzymes contribute to cellular metabolism, and mutations to specific catalytic residues result in the neomorphic production of D-2-hydroxyglutarate (D-2-HG). The accumulation of D-2-HG results in epigenetic alterations, oncogenesis and impacts the tumor microenvironment via immunological modulations. Here, we summarize the molecular, cellular, and clinical implications of IDH mutations in gliomas as well as current diagnostic techniques.