Genetically Shared Signatures Between COVID-19 and Cancer Identified Through In Silico Case-Control Analysis.

Cancer patients are highly susceptible to infectious diseases due to malignancy- and treatment-induced immunosuppression. The coronavirus disease 2019 (COVID-19) pandemic highlighted this vulnerability, particularly in aggressive tumors such as triple-negative breast cancer (TNBC) and clear cell renal cell carcinoma (ccRCC). However, the molecular mechanisms linking cancer progression with COVID-19 severity remain poorly defined. This study aimed to identify shared molecular signatures between COVID-19 and TNBC, breast cancer, and ccRCC using integrative bioinformatics approaches. A comprehensive in silico case-control analysis was conducted using publicly available GEO transcriptomic datasets (GSE164805, GSE139038, GSE45498, and GSE105261). Differentially expressed genes (DEGs) were identified by comparing mild and severe COVID-19 cases with each cancer type. Protein-protein interaction (PPI) networks were constructed to identify hub genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Regulatory networks involving microRNAs (miRNAs) and transcription factors (TFs) were also examined. Shared hub genes were identified across COVID-19 and cancer datasets, including IGF1, MMP9, and NOTCH1 in TNBC; TOP2A, PXN, and CCNB1 in breast cancer; and ASPM and TTK in ccRCC. These genes are linked to immune regulation, inflammation, cell cycle control, and tumor progression. Enrichment analyses revealed convergent pathways such as MAPK signaling, cytokine-cytokine receptor interaction, Ras signaling, and proteoglycans in cancer. Key regulatory molecules, including miR-145-5p, miR-192-5p, miR-335-5p, and transcription factors NFKB1, BRCA1, and TP53, modulated both viral and oncogenic processes. Severe COVID-19 was associated with enhanced inflammatory and proliferation-related signaling across all cancer types. This integrative, severity-stratified analysis identifies shared molecular and regulatory features linking severe COVID-19 with aggressive cancers, highlighting persistent immune activation and altered immune communication as common underlying themes without implying causality or clinical outcome effects. These findings provide a systems-level, hypothesis-generating framework for understanding virus-cancer interactions and may inform future biomarker discovery and immune-focused therapeutic strategies in vulnerable cancer populations.