Affiliation:
1. Cancer Genetics and Epigenetics Lab, Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad, Pakistan
Abstract
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 ∼60% 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.