Integrative Proteogenomic Characterization of Left‐Sided and Right‐Sided Colorectal Cancer

Distinguishing characteristics have been found in the left‐sided and right‐sided colorectal cancer (CRC), which have different embryonic origins, molecular and clinical features. These result in differences in the efficacy of targeted therapy and immunotherapy. Multi‐omics characterization, predicated upon tumor laterality, may facilitate a more precise and personalized approach to the treatment of patients with CRC. Encompassing whole‐exome, proteomics, and phosphoproteomics sequencing, we conducted a comprehensive investigation of tumor and matched normal adjacent tissues from a total of 80 pairs of patients with CRC. Results revealed that the pathogenesis of left‐sided CRC was predominantly associated with chromosomal instability, while right‐sided CRC was primarily linked to microsatellite instability. Regarding the tumor microenvironment, left‐sided CRC exhibited predominant microvascular endothelial cell proliferation, while right‐sided CRC displayed enhanced MHC Class II‐associated antigen presentation mediated by M1 macrophages. Additionally, the proportion of deficient mismatch repair that developed into microsatellite instability‐high was observed to be lower in the left‐sided CRC compared to the right‐sided, indicating divergent DNA damage repair systems between laterality subtypes that contribute to differential immunotherapy efficacy. This integrated proteogenomic study provides a comprehensive and nuanced understanding of the molecular heterogeneity between left‐ and right‐sided CRC, offering opportunities for optimizing these patients' treatment outcomes through tailored therapeutic strategies.