Proteogenomic Analysis of Human Colon Cancer Reveals New Therapeutic Opportunities

AUTHORS

Vasaikar SSuhas , Huang CChen , Wang XXiaojing , Petyuk VAVladislav A , Savage SRSara R , Wen BBo , Dou YYongchao , Zhang YYun , Shi ZZhiao , Arshad OAOsama A , Gritsenko MAMarina A , Zimmerman LJLisa J , McDermott JEJason E , Clauss TRTherese R , Moore RJRonald J , Zhao RRui , Monroe MEMatthew E , Wang YTYi-Ting , Chambers MCMatthew C , Slebos RJCRobbert J C , Lau KSKen S , Mo QQianxing , Ding LLi , Ellis MMatthew , Thiagarajan MMathangi , Kinsinger CRChristopher R , Rodriguez HHenry , Smith RDRichard D , Rodland KDKarin D , Liebler DCDaniel C , Liu TTao , Zhang BBing , . Cell. 2019 4 25; 177(4). 1035-1049.e19

PMID: 31031003[PubMed].

ABSTRACT

We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog 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. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.