Abstract LB095: Chromosomal weak links in cancer: A/B compartment rewiring coupled to global DNA methylation alterations in gastric tumorigenesis

Abstract 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. Citation Format: Ashley Ramos-López, Sebastián Rodríguez-Torres, Laura Palmieri, Yanira González-Rodríguez, Robert Gilman, Martha H. Jahuira-Arias, Jaime Cok, Juan Combe, Gloria Vargas, William Prado, Mariana Brait, David Sidransky, Rafael Guerrero-Preston. Chromosomal weak links in cancer: A/B compartment rewiring coupled to global DNA methylation alterations in gastric tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB095.