PNNL

Abstract

We performed the first proteogenomic study on a prospectively collected colon cancer cohort to systematically identify new therapeutic opportunities. Comparative proteomic and phosphoproteomic analysis of paired tumor and adjacent normal samples produced a catalogue of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomic data revealed a dual role of RB1 hyperphosphorylation in promoting proliferation and repressing apoptosis in colon cancer, clarifying the long-standing puzzle of colon cancer-specific amplification of this tumor suppressor and highlighting a unique opportunity for targeting RB1 hyperphosphorylation in colon cancer. Proteomics identified an association between increased glycolysis and decreased CD8 T cell infiltration in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a target for overcoming subtype-specific immune evasion. Proteogenomics offers a new avenue for therapeutic discoveries.