A novel cachexia-related signature as predictor of prognosis and immune infiltration in colon adenocarcinoma

Colon adenocarcinoma (COAD) has high morbidity and mortality worldwide. Cachexia is a frequent complication of cancer that shortens survival, reduces quality of life, and lowers tolerance to treatment, yet its role in COAD and the genes that drive it are still poorly defined. We therefore assessed whether a cachexia-related gene (CRG) signature can predict outcome in COAD. Unsupervised clustering of CRG expression profiles from the TCGA and GEO databases was performed to identify molecular subtypes and differentially expressed genes. Univariate, Lasso, and multivariate Cox regression analyses were used to create prognostic models. COAD patients were stratified into high-risk and low-risk subgroups, and the prognostic efficacy of the model was evaluated through survival analysis, ROC curves, and nomograms. Differences in immune cell infiltration and risk scores were compared across risk categories. Biological experiments were then conducted to explore the functions of candidate genes. The CRG risk score model, comprising TIMP1, CDKN2A, CTLA4, AMBP, SLC2A3, IL13RA2, LINGO1, ASNS, and MAPK12, independently predicted COAD prognosis. Clinical correlation and ROC curve analyses confirmed its accuracy in forecasting 1-, 3-, and 5-year survival. Drug sensitivity analysis based on the GDSC database showed that the high-risk group was more sensitive to Nilotinib, Erlotinib, and Navitoclax. In vitro, MAPK12 overexpression promoted the secretion of cachexia-related cytokines IL-6 and CXCL8 by endothelial cells. We developed a CRG-related risk signature for the early diagnosis and classification of COAD patients that offers potential targets for individualized treatment. Furthermore, our findings indicate that MAPK12 serves as a novel biomarker and therapeutic target for COAD.