Age-associated genomic instability and inflammatory pathway activation: A pan-cancer multi-omics analysis of the TITANIA framework.

Abstract

2583 Background: Aging is associated with increased cancer incidence and altered tumor biology, yet molecular mechanisms underlying age-related differences remain poorly characterized at the multi-omics level. We hypothesized that elderly patients may exhibit coordinated increases in genomic instability and inflammatory pathway activation. Methods: We performed integrated multi-omics analysis comprising whole genome sequencing, RNA sequencing, and data-independent acquisition mass spectrometry-based proteomics on 153 treatment-naive patients across six cancer types (colorectal cancer n=52, gastric n=19, kidney n=32, non-small cell lung cancer n=27, ovarian n=19, liver n=4). The TITANIA study provided matched tumor and normal tissue specimens with standardized collection protocols (median cold ischemia time: 12 minutes). Patients were stratified by age (≤60 years, n=40; >60 years, n=113). Inflammation scores were calculated using ssGSEA of six Hallmark inflammatory pathways. Tumor microenvironment subtypes were identified using xCell deconvolution followed by k-means clustering (k=3). Results: Tumor mutation burden (TMB) showed a significant positive correlation with age (Spearman ρ=0.334, P<0.001), with elderly patients demonstrating higher median TMB than younger patients (4.55 vs 2.84 mut/Mb, P<0.001). Inflammation scores showed positive correlations with age in tumor tissues at both RNA (ρ=0.223, P=0.01) and protein (ρ=0.233, P=0.005) levels. Normal tissue inflammation correlated with paired tumor TMB (RNA: ρ=0.283, P=0.027; Protein: ρ=0.387, P<0.001), raising the possibility that systemic inflammaging may be associated with tumor genomic instability. TME clustering identified three subtypes: Immune-Hot (n=14), Immune-Cold (n=92), and Vascular-Rich (n=30). Notably, all patients in the Immune-Hot cluster were elderly (>60 years). TMB positively correlated with B cells, neutrophils, and M1 macrophages, while negatively correlated with stromal score and endothelial cells. The EPITHELIAL_MESENCHYMAL_TRANSITION pathway showed potential as a prognostic marker at both omics levels (C-index: RNA 0.63, Protein 0.61), though further validation is warranted. Conclusions: This pan-cancer multi-omics analysis demonstrates age-dependent genomic instability coupled with inflammatory pathway activation in both tumor and normal tissues, consistent with the inflammaging hypothesis. The novel finding that normal tissue inflammation correlates with tumor TMB suggests systemic inflammaging may contribute to tumor evolution, with potential implications for age-adapted immunotherapy strategies.