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.