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.

Fan Zhang;Qilin Zhang;Jiajun Zhu;Boyuan Yao;Chi Ma;Nidan Qiao;Shiman He;Zhao Ye;Yunzhi Wang;Rui Han;Jinwen Feng;Yongfei Wang;Zhaoyu Qin;Zengyi Ma;Kai Li;Yichao Zhang;Sha Tian;Zhengyuan Chen;Subei Tan;Yue Wu;Peng Ran;Ye Wang;Chen Ding;Yao Zhao

State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development,School of Life Sciences,Institute of Biomedical Sciences,Human Phenome Institute,Zhongshan Hospital,Fudan University,Shanghai,China;Department of Neurosurgery,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai,China;National Center for Neurological Disorders,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai,China;State Key Laboratory of Cell Differentiation and Regulation,Henan International Joint Laboratory of Pulmonary Fibrosis,Henan center for outstanding overseas scientists of pulmonary fibrosis,College of Life Science,Institute of Biomedical Science,Henan Normal University,Xinxiang,Henan,China;Department of Radiology,Huashan Hospital,Shanghai Medical College,Fudan University,Shanghai,China;State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science,Institutes of Brain Science,Fudan University,Shanghai,China;Shanghai Key laboratory of Brain Function Restoration and Neural Regeneration,Shanghai,China;Neurosurgical Institute of Fudan University,Shanghai,China;National Clinical Research Center for Aging and Medicine,Huashan Hospital,Fudan University,Shanghai,China

细胞研究（英文版）

[1]Fan Zhang;Qilin Zhang;Jiajun Zhu;Boyuan Yao;Chi Ma;Nidan Qiao;Shiman He;Zhao Ye;Yunzhi Wang;Rui Han;Jinwen Feng;Yongfei Wang;Zhaoyu Qin;Zengyi Ma;Kai Li;Yichao Zhang;Sha Tian;Zhengyuan Chen;Subei Tan;Yue Wu;Peng Ran;Ye Wang;Chen Ding;Yao Zhao-.Integrated proteogenomic characterization across major histological types of pituitary neuroendocrine tumors)[J].细胞研究（英文版）,2022(12):1047-1067

proteogenomic,PitNETs

Integrated,characterization,across,major,histological,pituitary,neuroendocrine,tumors,Pituitary,one,most,common,intracranial,Due,its,extensive,heterogeneity,lack,high,quality,tissues,biomarker,discovery,causative,molecular,mechanisms,are,far,from,being,fully,defined,Therefore,more,studies,needed,current,clinicopathological,classification,system,advanced,treatment,strategies,such,targeted,immunotherapy,yet,explored,Here,performed,largest,integrative,genomics,transcriptomics,phosphoproteomics,analysis,reported,date,cohort,patients,Genomics,data,indicate,that,GNAS,copy,number,gain,can,serve,reliable,diagnostic,hyperproliferation,PIT1,lineage,Proteomics,identified,clusters,among,which,overexpressing,epithelial,mesenchymal,transition,EMT,markers,clustered,into,invasive,subgroup,Further,potential,therapeutic,targets,including,CDK6,TWIST1,VEGFR2,different,Immune,subtyping,application,association,between,alterations,JAK1,STAT1,PDL1,axis,immune,exhaustion,changes,JAK3,STAT6,FOS,JUN,infiltration,These,alternations,various,subtypes,were,further,confirmed,independent,This,traditional,boundaries,improves,our,understanding,pathophysiology,suggests,novel

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