Background <p>Colon cancer (CC) presents significant molecular heterogeneity, complicating our understanding of its initiation and progression. Identifying CC-associated genes and their interactions is crucial for improving diagnostics and therapeutics. However, current gene analysis methods struggle to holistically capture complex gene interactions due to their inherent complexity.</p> Method <p>We propose a novel, simple, and scalable method called <span>Efficient Differential Latent Network Analysis</span> (EDLNA) for detecting alterations in gene interactions using latent co-expression patterns. Our approach applies non-negative matrix factorization to construct separate latent gene networks for normal and cancer samples. We then identify differential interactions, followed by protein-protein interaction network and transcription factor (TF) analyses to detect functional modules and regulatory relationships.</p> Results <p>We evaluated EDLNA against conventional methods using both simulated and colon cancer gene expression data (GSE44076, GSE50760). In simulation studies, EDLNA was significantly faster among differential network analysis techniques while maintaining comparable accuracy. When applied to colon cancer data, our method outperformed differential gene expression analysis in identifying biologically relevant gene clusters and stage-specific traits.</p> Conclusions <p>EDLNA provides an efficient and scalable framework for identifying stage-specific gene interactions that bridge molecular mechanisms with clinical phenotypes. These findings underscore its potential for discovering novel biomarkers and advancing targeted therapies in colon cancer.</p>