Identification of Core SASP-Related Genes TGFBI and ANXA6 for Diagnosing Ulcerative Colitis-Related Colorectal Cancer Through Machine Learning

PURPOSE: To explore the role of senescence-associated secretory phenotype (SASP) in ulcerative colitis-related colorectal cancer (UCRCC) precision diagnosis and pathogenesis. METHODS: In this study, we first screened the SASP-related genes (SASPRGs) in the ulcerative colitis (UC) and colorectal cancer (CRC) datasets using differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA). Subsequently, the core SASPRGs were further identified using 113 combinations of 10 machine learning algorithms, and evaluating their expression levels, diagnostic efficacy, prognostic value, and relationship with immune cells. Expression patterns of core SASPRGs were analyzed using scRNA-seq, and a molecular regulatory network was constructed. In addition, immunotherapy response and drug sensitivity analysis were conducted to screen therapeutic drugs targeting core SASPRGs. Finally, their expression levels were validated through in vivo experiments. RESULTS: We identified 12 core SASPRGs, among which TGFBI and ANXA6 exhibited satisfactory diagnostic efficacy and prognostic value for UC and CRC. ANXA6 and TGFBI are highly expressed in monocytes and fibroblasts, and are associated with the infiltration of multiple immune cells. In addition, high TGFBI and ANXA6 groups showed poor responses to immunotherapy. The candidate therapeutic drugs screened by drug sensitivity analysis showed good binding ability with ANXA6 and TGFBI. Finally, the expression levels of TGFBI and ANXA6 were significantly increased in UC and CRC mouse models. CONCLUSION: Overall, TGFBI and ANXA6 are crucial in UCRCC, serving as novel diagnostic markers. They exhibit robust predictive capabilities on patient prognosis and immunotherapy response, offering actionable insights to optimize therapeutic decision-making and advance personalized treatment paradigms in UCRCC management.