Development of an application for colorectal cancer prediction using SDC2 and TFPI2 methylation: an opportunity for early and noninvasive diagnosis in Latin-America

Colorectal cancer remains a major public health challenge globally and within Latin-America, where expanding mortality rates are compounded by heterogeneous access to screening programs, healthcare infrastructure. While early detection is critical to improving survival rates, conventional fecal tests and colonoscopies face significant financial, logistical, and patient-adherence barriers in resource-limited settings. Epigenetic alterations, specifically promoter hypermethylation of CpG islands, occur early during the adenoma-carcinoma sequence and provide stable, highly sensitive targets for noninvasive molecular diagnostics. In this Perspective, we discuss the molecular rationale and complementary diagnostic value of combining two robustly validated epigenetic biomarkers, Syndecan-2 (SDC2), which modulates epithelial integrity and signaling, and Tissue Factor Pathway Inhibitor-2 (TFPI2), a critical serine protease inhibitor regulating extracellular matrix remodeling. Transcriptional silencing of these genes through aberrant hypermethylation reflects distinct yet commentary pathways of colorectal carcinogenesis, providing the molecular foundation for the implementation strategy proposed herein. To overcome technical barriers that currently limit the broader adoption of methylation-based screening, we present the integration of validated quantitative real-time PCR (qPCR) methylation assays with ColoGuardIA, an open-source, lightweight, Shiny-based digital application developed by our group as an implementation-oriented proof-of-concept platform. ColoGuardIA facilitates the standardized interpretation of qPCR-derived cycle threshold (Ct) values generated by previously validated methylation tests. By helping bridge the gap between molecular oncology and decentralized clinical implementation, this framework represents a scalable strategy to support the adoption of noninvasive methylation-based screening approaches and improve access to early colorectal cancer detection in Latin-America.