美国纽约大学格David Fenyö、西北太平洋国家实验室Tao Liu和Karin D. Rodland、贝勒医学院Bing Zhang以及美国南佛罗里达大学Matthew L. Anderson团队合作利用蛋白质基因组学图谱揭示子宫内膜癌(EC)的药物通路。相关论文于2023年8月10日发表于国际顶尖学术期刊《癌细胞》杂志上。

他们使用10种不同的组学平台对一个前瞻性EC队列进行了特征描述，该队列包含138个肿瘤和20个富集的正常组织。两种多肽的靶向定量可以预测抗原加工和递呈机制活性，并可能为患者选择免疫治疗提供信息。在患者和细胞系中MYC活性与二甲双胍治疗之间的关联分析表明，二甲双胍治疗在MYC活性升高的非糖尿病患者中具有潜在作用。PIK3R1框架插入缺失突变与AKT磷酸化升高和对AKT抑制剂的敏感性增加有关。

CTNNB1热点突变集中在介导ps45诱导的β-catenin降解的磷酸化位点附近，这可能导致Wnt-FZD拮抗剂无效。深度学习可以准确预测EC的亚型和突变，这可能有助于快速诊断。总的来说，本研究确定了分子和影像学标记物，可以进一步研究指导患者分层，以更精确地治疗EC。

附：英文原文

Title: Proteogenomic insights suggest druggable pathways in endometrial carcinoma

Author: Yongchao Dou, Lizabeth Katsnelson, Marina A. Gritsenko, Yingwei Hu, Boris Reva, Runyu Hong, Yi-Ting Wang, Iga Kolodziejczak, Rita Jui-Hsien Lu, Chia-Feng Tsai, Wen Bu, Wenke Liu, Xiaofang Guo, Eunkyung An, Rebecca C. Arend, Jasmin Bavarva, Lijun Chen, Rosalie K. Chu, Andrzej Czekański, Teresa Davoli, Elizabeth G. Demicco, Deborah DeLair, Kelly Devereaux, Saravana M. Dhanasekaran, Peter Dottino, Bailee Dover, Thomas L. Fillmore, McKenzie Foxall, Catherine E. Hermann, Tara Hiltke, Galen Hostetter, Marcin Jdryka, Scott D. Jewell, Isabelle Johnson, Andrea G. Kahn, Amy T. Ku, Chandan Kumar-Sinha, Pawe Kurzawa, Alexander J. Lazar, Rossana Lazcano, Jonathan T. Lei, Yi Li, Yuxing Liao, Tung-Shing M. Lih, Tai-Tu Lin, John A. Martignetti, Ramya P. Masand, Rafa Matkowski, Wilson McKerrow, Mehdi Mesri, Matthew E. Monroe, Jamie Moon, Ronald J. Moore, Michael D. Nestor, Chelsea Newton, Tatiana Omelchenko, Gilbert S. Omenn, Samuel H. Payne, Vladislav A. Petyuk, Ana I. Robles, Henry Rodriguez, Kelly V. Ruggles, Dmitry Rykunov

Issue&Volume: 2023-08-10

Abstract: We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.

DOI: 10.1016/j.ccell.2023.07.007

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00247-7