Abstract
Metastatic colorectal cancer (mCRC) remains the second leading cause of cancer-related mortality, with treatment resistance posing a major challenge. Emerging evidence suggests that DNA methylation may contribute to therapy resistance. This project aims to develop a cost-effective, liquid biopsy-based biomarker assay integrating methylation and mutation profiling for longitudinal monitoring and therapy guidance in mCRC. Through an epigenome-wide analysis, I will identify differentially methylated CpG sites (DMCs) associated with tumor burden. With Oxford Nanopore Technology (ONT) sequencing, which enables simultaneous detection of mutations and methylation changes, I will uncover novel resistance-associated biomarkers. Selected DMCs will be incorporated into the IMPRESS technology using single-molecule Molecular Inversion Probes (smMIPs) targeting CpG sites, alongside smMIPs targeting established resistance mutations. Additionally, a standardized methylation metric will be developed to track tumor progression over time. The assay will be optimized and validated using plasma samples from the FOLICOLOR trial, a well-characterized longitudinal patient cohort, and further strengthened by an international collaboration with James Cancer Center (Ohio, USA), providing additional samples. With direct access to high-quality patient samples, this project aims to deliver a scalable and affordable biomarker test, advancing precision medicine in mCRC and reducing healthcare costs.
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