Multi-Omic Analysis of Putative Cellular Senescence-Associated Genes on the Risk of Pan-Cancer

Cellular senescence plays a critical role in physiological and pathological processes. This study aims to elucidate the contribution of cellular senescence-related genes to disease etiology. We investigated a cohort study of 439,501 individuals, which included 22 cancers and 9 non-cancer diseases. We found that HLA-E and HLA-G-associated senescence in epithelial and immune cells were specific oncogenic factors for prostate and lung cancers. MAP2K4 was implicated as a risk factor for breast cancer, while ZFP36L1 and STAT3 were associated with a reduced risk of inflammatory bowel disease (IBD). Notably, ETS2-mediated inhibition of the senescence-associated secretory phenotype (SASP) was associated with decreased disease risk. Furthermore, single-cell level analysis confirmed that the dynamics of these marked gene expressions in immune cells was related to reduced disease risk, while upregulation in epithelial cells correlated with increased disease risk. In parallel, co-localization analyses corroborated these associations, explaining potential regulatory mechanisms underlying disease risk variants. These findings enhance our understanding of how cellular senescence works on disease susceptibility and provide potential targets for therapeutic interventions and precision medicine approaches.