Pan-cancer analysis and oncogenic implications of MGAM and MGAM2: Toward precision oncology and drug repurposing in colorectal cancer

Cancer remains a major global health challenge, with high prevalence and mortality rates emphasizing the urgent need for innovative treatment strategies. Although precision oncology offers tailored therapies based on genetic profiles, the clinical translation of genomic insights has been slow. Drug repurposing, using existing FDA-approved drugs for new indications, presents a cost-effective and time-efficient alternative. This study investigates MGAM as a potential direct target of alpha-glucosidase inhibitors in colorectal cancer (CRC), explores its biomarker potential, and evaluates gene expression patterns across diverse cancers. Using RNA-Seq data from Recount3, Firebrowse, and gene set co-expression analysis databases, we analyzed the differential expression of MGAM and its paralog MGAM2 across 33 cancer types. We examined mutation profiles, methylation status, survival impact, immune cell infiltration, and drug-mRNA interactions. Validation was performed via real-time PCR and whole-exome sequencing (WES) in CRC patients. MGAM and MGAM2 showed differential expression across multiple cancers, with MGAM2 upregulated and MGAM downregulated in gastrointestinal tumors. Both genes were linked to key cancer-related pathways, including metabolism, apoptosis, cell cycle regulation, and epithelial-mesenchymal transition. MGAM exhibited frequent mutations and aberrant methylation in several cancers. Their expression correlated with immune cell infiltration and drug sensitivity, highlighting potential for therapy planning. Diagnostic modeling showed over 80% accuracy. In CRC patients, MGAM downregulation was confirmed in 64 samples, and WES revealed a novel MGAM mutation (rs2960746). These findings underscore MGAM and MGAM2 as promising biomarkers and therapeutic targets, supporting their relevance in advancing personalized oncology.