Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
Cell. 2019 May 2;177(4):1035-1049.e19. doi: 10.1016/j.cell.2019.03.030. Epub 2019 Apr 25.
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.
我们对一个前瞻性收集的结肠癌队列进行了首次蛋白质基因组学研究。对配对的肿瘤和正常相邻组织进行比较蛋白质组学和磷酸化蛋白质组学分析，产生了一个与结肠癌相关的蛋白质和磷酸化位点目录，包括已知和推测的新生物标志物、药物靶点和癌症/睾丸抗原。蛋白质基因组学整合不仅优先考虑了基因组推断的靶标，如拷贝数驱动和突变衍生的新抗原，还产生了新的发现。磷酸化蛋白质组学数据将 Rb 磷酸化与结肠癌中增殖增加和凋亡减少相关联，这解释了为什么这个经典的肿瘤抑制因子在结肠癌中扩增，并为在结肠癌中靶向 Rb 磷酸化提供了依据。蛋白质组学鉴定出微卫星不稳定性高（MSI-H）肿瘤中 CD8 T 细胞浸润减少和糖酵解增加之间的关联，表明糖酵解可能是克服 MSI-H 肿瘤对免疫检查点阻断的耐药性的潜在靶点。蛋白质基因组学为生物学发现和治疗开发提供了新的途径。
