Genetic underpinnings of type-2 diabetes (T2D) with colorectal cancer (CRC): In-silico discovery of common molecular signatures, pathogenetic processes and therapeutic candidates.

Type-2 diabetes (T2D) is a risk factor for colorectal cancer (CRC) and the incidence rate of CRC in T2D patients is significantly higher than in control patients. It may be associated with the overlapping dysregulated genetic factors. The management of CRC becomes complicated with T2D compare to without T2D due to the conflict of therapeutic priorities for both diseases.​ However, studies on overlapping dysregulated genetic factors and their therapeutic priorities during their co-incidence/existence, are very limited. This study aimed to identify those overlapping dysregulated genetic factors with their functions, pathways and regulators through which T2D may stimulate the development and progression of CRC, for exploring effective shared drug therapies (polypharmacological agents) against both diseases, since a disease specific drug may conflict with other diseases during their co-existence. In order to explore repurposable common drugs for both T2D and CRC, we identified both diseases causing top-ranked 8 sKGs (CD44, COL18A1, CLDN5, PLS3, PTK2, THBS1, CAV1, and EFEMP1) as the drug targets through transcriptomics analysis. The relationship of sKGs with T2D and CRC were also verified through the literature review, expression analysis with independent datasets, functional enrichment analysis with KEGG-pathways and GO-terms, regulatory network analysis with microRNAs and transcription factors (TFs), DNA methylation and immune infiltration analysis based on independent databases. Finally, sKGs-guided top-ordered four candidate drugs (irinotecan, leucovorincalcium, regorafenib and Fenretinide) were recommended as the shared treatments for both CRC and T2D during their co-existence. The recommended drug therapy might be effective to reduce drug burden from the patients. Therefore, the findings demand experimental and clinical validations for taking a proper treatment plan against CRC with T2D as comorbidity.