RESUMO
BACKGROUND: IDH1 mutations are common in many cancers, however, their role in promoting the Warburg effect remains elusive. This study elucidates the putative involvement of mutant-IDH1 in regulating hypoxia-inducible factor (HIF1-α) and Sine-Oculis Homeobox-1 (SIX-1) expression. METHODOLOGY: Genetic screening was performed using the ARMS-PCR in acute myeloid leukemia (AML), brain, and breast cancer (BC) cohorts, while transcript expression was determined using qPCR. Further, a meta-analysis of risk factors associated with the R132 mutation was performed. RESULTS: Approximately 32% of AML and â¼60% of glioma cases were mutants, while no mutation was found in the BC cohort. 'AA' and TT' were associated with higher disease risk (OR = 12.18 & 4.68) in AML and had significantly upregulated IDH1 expression. Moreover, downregulated HIF1-α and upregulated SIX-1 expression was also observed in these patients, suggesting that mutant-IDH1 may alter glucose metabolism. Perturbed IDH1 and HIF-α levels exhibited poor prognosis in univariate and multivariate analysis, while age and gender were found to be contributory factors as well. Based on the ROC model, these had a good potential to be used as prognostic markers. A significant variation in frequencies of R132 mutations in AML among different populations was observed. Cytogenesis (R2 = 12.2%), NMP1 mutation status (R2 = 18.5%), and ethnic contributions (R2 = 73.21%) were critical moderators underlying these mutations. Women had a higher risk of R132 mutation (HR = 1.3, P < 0.04). The pooled prevalence was calculated to be 0.29 (95% CI 0.26-0.33, P < 0.01), indicating that IDH1 mutations are a significant prognostic factor in AML. CONCLUSION: IDH1 and HIF1-α profiles are linked to poor survival and prognosis, while high SIX-1 expression in IDH1 mutants suggests a role in leukemic transformation and therapy response in AML.
IDH1 mutations are common in many types of cancer, but scientists have not fully understood how they contribute to the Warburg effect - a process that alters glucose metabolism in cells. In this study, we evaluate the association between mutant-IDH1 and HIF1 as well as SIX-1 gene expression. We analyzed genetic data from patients with brain cancer, breast cancer, and acute myeloid leukemia (AML), and found that roughly 32% of AML cases and 60% of glioma cases had IDH1 mutations, while no mutations were found in breast cancer. Patients with mutant genotypes had a higher risk of disease and showed upregulated IDH1 expression. They also had downregulated HIF1 and upregulated SIX-1 expression, suggesting that mutant-IDH1 can change glucose metabolism in cancer cells. Patients with abnormal IDH1 and HIF1 levels were more likely to have a poor prognosis. Further, we identified several risk factors that can influence IDH1 mutations, including cytogenesis, NMP1 mutation status, and ethnicity. The researchers calculated that IDH1 mutations are a significant factor in predicting outcomes for AML.