Prognostic significance of IDH1 promoter methylation and associated genome-wide alterations in breast cancer

Dysregulation of IDH1, a key metabolic enzyme, is widely reported across cancers and affects both tumor biology and patient prognosis. However, its regulation and associated epigenetic alterations in breast cancer (BC) remain unclear. This study examined methylation of two CpG islands (I1, I2) within the IDH1 promoter and a putative distal enhancer in clinical BC samples, correlating these patterns with IDH1 expression and clinicopathological features. Expression of PFKP, HIF-1α, and SIX1 was profiled to assess metabolic and developmental pathways. Additionally, genome-wide methylation analysis of IDH1-stratified TCGA-BRCA cohorts was performed to identify topological probe clusters with potential regulatory relevance. Twelve CpGs within I1 (- 109 to - 205 bp) were significantly hypermethylated in BC and showed an association with reduced IDH1 expression and a trend toward improved survival in this cohort, outperforming IDH1 expression in ROC analysis. I1 methylation was markedly higher in postmenopausal, metastatic, and TNBC cases and mapping to key transcription factor binding sites (CTCF, MYC, STAT3), suggesting disruption of regulatory complexes. PFKP, HIF-1α, and SIX1 were upregulated in these cases, indicating metabolic and developmental reprogramming. Genome-wide methylation analysis of IDH1-stratified TCGA cohorts revealed widespread alterations, with 33% of differentially methylated probes mapping to intergenic regions. High-density clusters on chromosomes 13 (85.7/kb) and 6 (32.5/kb), along with hypermethylation of CLDN18 and HRNBP3 promoters, implicated chromatin remodeling and splicing as frequent IDH1-associated events. Network analysis identified 332 hub genes, including HNRNPA1 and CBX5, reinforcing the role of epigenetic deregulation in BC pathogenesis. These findings suggest that IDH1 promoter methylation may hold prognostic relevance and suggest that altered IDH1 regulation contributes to broader epigenetic and chromatin remodeling events in BC.