Multilevel proteomic analyses reveal molecular diversity between diffuse-type and intestinal-type gastric cancer

Wenhao Shi, Yushen Wang, Chen Xu, Yan Li, Sai Ge, Bin Bai, Kecheng Zhang, Yunzhi Wang, Nairen Zheng, Juan Wang, Shiqi Wang, Gang Ji, Jipeng Li, Yongzhan Nie, Wenquan Liang, Xiaosong Wu, Jianxin Cui, Yi Wang, Lin Chen (), Qingchuan Zhao (), Lin Shen (), Fuchu He (), Jun Qin () and Chen Ding ()
Additional contact information
Wenhao Shi: Tsinghua University
Yushen Wang: Tsinghua University
Chen Xu: Zhongshan Hospital, Fudan University
Yan Li: School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University
Sai Ge: Peking University Cancer Hospital and Institute
Bin Bai: Xijing Hospital of Digestive Diseases, Fourth Military Medical University
Kecheng Zhang: Chinese PLA General Hospital First Medical Center
Yunzhi Wang: School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University
Nairen Zheng: Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX center, Beijing), Beijing Institute of Lifeomics
Juan Wang: Xijing Hospital of Digestive Diseases, Fourth Military Medical University
Shiqi Wang: Xijing Hospital of Digestive Diseases, Fourth Military Medical University
Gang Ji: Xijing Hospital of Digestive Diseases, Fourth Military Medical University
Jipeng Li: Xijing Hospital of Digestive Diseases, Fourth Military Medical University
Yongzhan Nie: Xijing Hospital of Digestive Diseases, Fourth Military Medical University
Wenquan Liang: Chinese PLA General Hospital First Medical Center
Xiaosong Wu: Chinese PLA General Hospital First Medical Center
Jianxin Cui: Chinese PLA General Hospital First Medical Center
Yi Wang: Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX center, Beijing), Beijing Institute of Lifeomics
Lin Chen: Chinese PLA General Hospital First Medical Center
Qingchuan Zhao: Xijing Hospital of Digestive Diseases, Fourth Military Medical University
Lin Shen: Peking University Cancer Hospital and Institute
Fuchu He: Tsinghua University
Jun Qin: Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX center, Beijing), Beijing Institute of Lifeomics
Chen Ding: Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX center, Beijing), Beijing Institute of Lifeomics

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract Diffuse-type gastric cancer (DGC) and intestinal-type gastric cancer (IGC) are the major histological types of gastric cancer (GC). The molecular mechanism underlying DGC and IGC differences are poorly understood. In this research, we carry out multilevel proteomic analyses, including proteome, phospho-proteome, and transcription factor (TF) activity profiles, of 196 cases covering DGC and IGC in Chinese patients. Integrative proteogenomic analysis reveals ARIDIA mutation associated with opposite prognostic effects between DGC and IGC, via diverse influences on their corresponding proteomes. Systematical comparison and consensus clustering analysis identify three subtypes of DGC and IGC, respectively, based on distinct patterns of the cell cycle, extracellular matrix organization, and immune response-related proteins expression. TF activity-based subtypes demonstrate that the disease progressions of DGC and IGC were regulated by SWI/SNF and NFKB complexes. Furthermore, inferred immune cell infiltration and immune clustering show Th1/Th2 ratio is an indicator for immunotherapeutic effectiveness, which is validated in an independent GC anti-PD1 therapeutic patient group. Our multilevel proteomic analyses enable a more comprehensive understanding of GC and can further advance the precision medicine.

Date: 2023
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DOI: 10.1038/s41467-023-35797-6

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