Identification of Subtypes and a Prognostic Gene Signature in Colon Cancer Using Cell Differentiation Trajectories

Research on the heterogeneity of colon cancer (CC) cells is limited. This study aimed to explore the CC cell differentiation trajectory and its clinical implication and to construct a prognostic risk scoring (RS) signature based on CC differentiation-related genes (CDRGs). Cell trajectory analysis was conducted on the GSE148345 dataset, and CDRG-based molecular subtypes were identified from the GSE39582 dataset. A CDRG-based prognostic RS signature was constructed using The Cancer Genome Atlas as the training set and GSE39582 as the validation set. Two subsets with distinct differentiation states, involving 40 hub CDRGs regulated by YY1 and EGR2, were identified by single-cell RNA sequencing data, of which subset I was related to hypoxia, metabolic disorders, and inflammation, and subset II was associated with immune responses and ferroptosis. The CDRG-based molecular subtypes could successfully predict the clinical outcomes of the patients, the tumor microenvironment status, the immune infiltration status, and the potential response to immunotherapy and chemotherapy. A nomogram integrating a five-CDRG-based RS signature and prognostic clinicopathological characteristics could successfully predict overall survival, with strong predictive performance and high accuracy. The study emphasizes the relevance of CC cell differentiation for predicting the prognosis and therapeutic response of patients to immunotherapy and chemotherapy and proposes a promising direction for CC treatment and clinical decision-making.