Tumorigenesis occurs due to changes in both coding and non-coding regions of the genome. While researchers have studied protein-coding mutations in detail, the role of non-coding variants is less understood. In this study, we employed a computational framework to investigate changes in the dark DNA, including intronic single nucleotide variants (SNVs) and copy number variations (CNVs), in genes on human chromosome 1 (T2T-CHM13v2.0 assembly). We conducted expression profiling, followed by enrichment analysis, mutational mapping, CNV annotation, and drug-gene interaction studies. To fine-tune the Notch pathway, we docked NOTCH2 harboring an intronic single nucleotide variant (SNV) with six curcuma molecules and recorded the binding affinity. Protein-protein interaction (PPI) networks, along with enrichment analysis, identified 9 genes involved in various oncogenic pathways. The hubs identified were pivotal for cancer progression. CNVs that affect regulatory elements, especially promoters, enhancers, and epigenetically modified accessible regions, were strongly linked to changes in the expression of NOTCH2 and NRAS. Drug-gene interaction analysis highlighted Tazarotene (TP73) and Odevixibat (NOTCH2) as high-priority candidates for therapeutic repurposing. Docking studies revealed promising binding conformations and strong interactions between the modeled NOTCH2 protein and selected ligands, suggesting their potential as modulators of oncogenic pathways. Collectively, these findings underscore that non-coding structural alterations play a critical role in regulating cancer pathways and represent promising biomarkers and therapeutic targets in solid tumors.
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