Paper_5: 子宫内膜癌的蛋白基因组学特征

Highlights

1. Proteogenomics provides new insights into oncogenic signaling in endometrial carcinoma
2. Global acetylome and phosphoproteome surveys identify new regulatory mechanisms
3. QKI, circRNAs, and miRNAs form a potential feedback loop to promote EMT
4. Antigen presentation defects may render MSI tumors resistant to checkpoint blockade

Summary

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets.

Highlights

1. 蛋白基因组学为理解子宫内膜癌的致癌信号提供了新的角度
2. 通过对全局性的乙酰化、磷酸化蛋白组学进行研究鉴定出了新的调控机制
3. QKI, circRNAs, 和miRNAs形成潜在的反馈回路以提高EMT
4. 抗原呈递能力的缺失可能导致MSI肿瘤对检查点阻断疗法产生抵抗

Summary

针对95个子宫内膜癌样本，其中包括83个子宫内膜样肿瘤和12个浆液性肿瘤，进行了全面的蛋白基因组学描述。分析揭示了可能存在新的p53、 Wnt/β-catenin通路的干扰后果，鉴定了circRNAs在上皮-间充质细胞转换过程中的潜在作用，提供了临床和基因组学分类上的蛋白marker，这其中包括已知可成药通路的一些关系。全基因组的乙酰化检测为联系Wnt信号和组蛋白乙酰化的调节机制提供了新的洞见。我们也讨论了肿瘤免疫谱图，包括免疫原性的改变、新生抗原、常见的肿瘤抗原、免疫微环境，这些都有助于确定免疫治疗的决策。总的来说,我们的多组学分析为研究人员和临床工作者提供了非常有价值的资源，鉴定了在子宫内膜癌发生过程中新的分子水平的关系，同时提供了鉴定潜在治疗靶标的新方法。