Chromosomal weak links in cancer: A/B compartment rewiring coupled to global DNA methylation alterations in gastric tumorigenesis

Three-dimensional genome organization into A/B compartments constrains gene regulation, mutation rate, and epigenetic stability. However, how cancer-associated global DNA methylation alterations intersect with higher-order chromatin architecture to generate chromosomal vulnerabilities remains poorly understood. Building on the concept that long-range correlations in DNA methylation reliably reconstruct A/B compartments genome-wide, we developed an integrative epigenomic framework to identify “chromosomal weak links”: genomic regions prone to coordinated compartment instability and epigenetic disruption in cancer. We analyzed Illumina DNA methylation profiles from gastric cancer and matched non-malignant gastritis samples derived from two independent cohorts, including a Latin American (Peru) series and The Cancer Genome Atlas (TCGA). Using correlation-based eigenvector decomposition at megabase scale, we inferred A/B compartment states across all chromosomes and quantified compartment strength, switching frequency, and fragmentation. Comparative analyses revealed pervasive but non-random compartment remodeling in gastric cancer, with selective weakening of normally stable B (closed) compartments and focal A↔B switching events that were highly concordant between cohorts. These weak-link regions were strongly associated with global hypomethylation domains, intermediate methylation variability, and reduced long-range correlation structure, consistent with erosion of repressive chromatin organization. Notably, recurrent compartment weakening localized to chromosomal segments harboring key gastric cancer genes, including TP53 , ARID1A , LRP1B , and SYNE1 , where shifts toward a more open, unstable chromatin state were observed in tumors relative to gastritis controls. Integration with compartment-level metrics revealed that these loci reside at boundaries or low-magnitude eigenvector regions, suggesting intrinsic architectural fragility. Collectively, our results demonstrate that global DNA methylation alterations in cancer are tightly coupled to large-scale chromatin compartment reorganization, uncovering reproducible chromosomal weak links that may predispose regions to genomic instability and dysregulated gene control. This work establishes A/B compartment-methylation coupling as a scalable strategy to map cancer-specific vulnerabilities directly from epigenetic data, with potential implications for risk stratification and therapeutic targeting.