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

  • Nat Commun. 2023 Feb 14;14(1):835. doi: 10.1038/s41467-023-35797-6.
Wenhao Shi  #  1  2 ,  Yushen Wang  #  1  2 ,  Chen Xu  #  3 ,  Yan Li  #  4 ,  Sai Ge  5 ,  Bin Bai  6 ,  Kecheng Zhang  7 ,  Yunzhi Wang  4 ,  Nairen Zheng  2 ,  Juan Wang  6 ,  Shiqi Wang  6 ,  Gang Ji  6 ,  Jipeng Li  6 ,  Yongzhan Nie  6 ,  Wenquan Liang  7 ,  Xiaosong Wu  7 ,  Jianxin Cui  7 ,  Yi Wang  2 ,  Lin Chen  8 ,  Qingchuan Zhao  9 ,  Lin Shen  10 ,  Fuchu He  11  12  13 ,  Jun Qin  14  15 ,  Chen Ding  16  17
Affiliations
  • 1. School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 2. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX center, Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
  • 3. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 4. 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, 200433, China.
  • 5. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, 100142, China.
  • 6. State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China.
  • 7. Department of General Surgery & Institute of General Surgery, Chinese PLA General Hospital First Medical Center, Beijing, 100853, China.
  • 8. Department of General Surgery & Institute of General Surgery, Chinese PLA General Hospital First Medical Center, Beijing, 100853, China. [email protected].
  • 9. State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, 710032, China. [email protected].
  • 10. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, 100142, China. [email protected].
  • 11. School of Life Sciences, Tsinghua University, Beijing, 100084, China. [email protected].
  • 12. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX center, Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China. [email protected].
  • 13. Research Unit of Proteomics Driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing, 102206, China. [email protected].
  • 14. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX center, Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China. [email protected].
  • 15. 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, 200433, China. [email protected].
  • 16. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (The PHOENIX center, Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China. [email protected].
  • 17. 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, 200433, China. [email protected].
  • # Contributed equally.
PMID: 36788224 DOI: 10.1038/s41467-023-35797-6
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.