Integrative Transcriptomics Reveals Immune–Metabolic and Signalling Crosstalk in a Diabetes-Like State of Colorectal Cancer
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Abstract
Diabetes mellitus (DM) and colorectal cancer (CRC) share metabolic and signalling alterations, suggesting that CRC transcriptomes may provide a systems-level framework for investigating DM-associated molecular programmes. Transcriptomic data from 988 CRC tumours across TCGA (n=534), CPTAC-2 (n=106), and Sidra-LUMC (n=348) cohorts were integrated. Five DM-related transcriptional signatures were quantified, and hyperglycaemia, insulin resistance, and mitochondrial dysfunction scores were integrated into a core composite DM-like score. Gene set enrichment analysis (GSEA), differential expression analysis, gene ontology enrichment analysis (GOEA), pathway ontology enrichment analysis (POEA), and disease ontology enrichment analysis (DOEA) were used to characterize the DM-like phenotype. CRC tumours exhibited heterogeneous DM-related transcriptional programmes. GSEA independently identified diabetes-associated pathways, including insulin resistance, β-cell destruction, type 1 diabetes, and immune-regulatory programmes. DM-like-high tumours showed enrichment of glucose and insulin signalling, mitochondrial dysfunction, and diabetes-associated clinical features and complications, including atherosclerosis, nephropathy, fatty liver disease, retinopathy, and neuropathy. CRC transcriptomes recapitulate multiple molecular features of DM and provide a systems-level framework for investigating diabetes-associated molecular alterations, biomarkers, and potential therapeutic targets.
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