垂体神经内分泌瘤（PitNET）是最常见的颅内肿瘤之一。由于其肿瘤的广泛异质性和生物标志物发现所需高质量组织的不足，其致病的分子机制远未被完全定义。因此，需要更多的研究来改善当前的临床病理分类系统，并探索定向治疗和免疫治疗等先进治疗策略。在这里，我们对200名PitNET患者进行了迄今为止规模最大的整合基因组学，转录组学，蛋白质组学和磷酸化蛋白组学分析。基因组数据表明，GNAS拷贝数增益可作为PIT1谱系的高增殖性的可靠诊断标志物。基于蛋白质组学的PitNET分类鉴定了7个簇，在其中，表达上皮-间充质转化标记的肿瘤群聚为更侵袭的亚组。进一步的分析鉴定了各个簇的潜在治疗靶点，包括CDK6，TWIST1，EGFR和VEGFR2。免疫亚型分类的探索显示，JAK1-STAT1-PDL1轴和免疫疲劳以及JAK3-STAT6-FOS/JUN轴和免疫浸润之间存在关联。这些鉴定的分子标志物和不同簇/亚型中的变化在750名PitNET患者的独立队列中进一步确认。这种跨越传统组织学边界的蛋白质组学分析提高了我们对PitNET病理生理学的当前理解，并提出了新的治疗靶点和策略。 ©2022年作者（们）。

Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial tumors. Due to its extensive tumor heterogeneity and the lack of high-quality tissues for biomarker discovery, the causative molecular mechanisms are far from being fully defined. Therefore, more studies are needed to improve the current clinicopathological classification system, and advanced treatment strategies such as targeted therapy and immunotherapy are yet to be explored. Here, we performed the largest integrative genomics, transcriptomics, proteomics, and phosphoproteomics analysis reported to date for a cohort of 200 PitNET patients. Genomics data indicate that GNAS copy number gain can serve as a reliable diagnostic marker for hyperproliferation of the PIT1 lineage. Proteomics-based classification of PitNETs identified 7 clusters, among which, tumors overexpressing epithelial-mesenchymal transition (EMT) markers clustered into a more invasive subgroup. Further analysis identified potential therapeutic targets, including CDK6, TWIST1, EGFR, and VEGFR2, for different clusters. Immune subtyping to explore the potential for application of immunotherapy in PitNET identified an association between alterations in the JAK1-STAT1-PDL1 axis and immune exhaustion, and between changes in the JAK3-STAT6-FOS/JUN axis and immune infiltration. These identified molecular markers and alternations in various clusters/subtypes were further confirmed in an independent cohort of 750 PitNET patients. This proteogenomic analysis across traditional histological boundaries improves our current understanding of PitNET pathophysiology and suggests novel therapeutic targets and strategies.© 2022. The Author(s).