image: (A) Unsupervised clustering of 112 GSRCC cases identified key proteins with significant differences between tumors and NATs, focusing on the top 100 proteins with a FC > 1.5 and P value < 0.05. (B) Principal component analysis (PCA) visualizes the distribution of the identified subtypes, alongside HER2, EBV, and MSI status. (C) The Cox proportional hazards regression model was used to evaluate the impact of the newly identified subtypes and clinical factors on patient prognosis, calculating the hazard ratio (HR). (D) The associations between the four proteomic subtypes and overall survival in 112 GSRCC patients were assessed using the log-rank test, with Kaplan-Meier plots illustrating overall survival differences across subtypes. (E) Kaplan-Meier survival analysis stratified by TNM stage was further evaluated by overall survival variations among GSRCC subtypes. (F) Gene Set Enrichment Analysis (GSEA) identified significantly enriched biological pathways across GSRCC subtypes, with normalized scores highlighting key functional processes (adjusted P value < 0.05). GSRCC, gastric signet ring cell carcinoma; NATs, normal adjacent tissues; EBV, Epstein-Barr virus; HER2, human epidermal growth factor receptor 2; MSI, microsatellite instability.
Credit: Zhiyuan Jin, Li Yuan, Yubo Ma, Zu Ye, Zhao Zhang, Yi Wang, Can Hu, Jinyun Dong, Xinuo Zhang, Zhiyuan Xu, Yian Du, Xiaoqing Guan, Guangzhao Pan, Sichao Tian, Juan Li, Ruiwen Zhang, Jiangjiang Qin, Xiangdong Cheng
Gastric signet ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer (GC) with unique epidemiological and pathogenic characteristics. Despite its clinical significance, large-scale proteomic studies on GSRCC remain scarce, limiting our molecular understanding of the disease. Advanced mass spectrometry (MS)-based proteomics is crucial for identifying key biomarkers and drug targets, thereby enabling more effective therapeutic strategies.
In a recent study published in Genes & Diseases, researchers from several institutions, including Tianjin University, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Fudan University, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province, Chinese Academy of Medical Sciences and Peking Union Medical College, and University of Houston, characterizes the proteomic features and molecular mechanisms of GSRCC to date.
Initially, the research team analyzed clinical data from over 10,000 patients with GC between January 2010 and December 2019. An in-depth proteomic analysis was conducted on tumor tissues from 112 GSRCC patients, each with over 70% signet ring cell content. Using advanced MS, the team identified 7322 proteins, establishing the largest tissue-specific peptide spectral library for GSRCC. Additionally, through unsupervised clustering, the team identified four novel proteomic subtypes of GSRCC: Metabolism (S-Mb), Microenvironment Dysregulation (S-Me), Migration (S-M) and Proliferation (S-PF).
Two key prognostic biomarkers were identified and validated in an independent cohort of 75 patients: PRDX2, a protein associated with favorable prognosis; and DDX27, linked to poor survival outcomes. Furthermore, proteomic profiling of 79 biomarker-negative GSRCC cases revealed marked tumor heterogeneity. Notably, unsupervised clustering identified three distinct proteomic clusters, with cluster 2 linked to the poorest prognosis.
Focusing on HER2-negative, EBV-negative, and pMMR GSRCC cases (LMT [Lack of Medical Treatment]-GSRCC), the study identified four potential drug targets: eukaryotic translation initiation factor 2 subunit gamma (EIF2S3), eukaryotic translation initiation factor 6 (EIF6), and nuclear factor kappa B subunit 2 (NFKB2). Remarkably, high expression of these proteins was associated with poor prognosis, underscoring their relevance as promising therapeutic candidates.
Interestingly, molecular docking and cytotoxicity testing singled out neratinib—a drug approved for breast cancer treatment—as the most promising candidate. Furthermore, in vitro and in vivo studies demonstrated neratinib’s potent ability to inhibit tumor growth, cell migration, and invasion, while promoting cancer cell apoptosis, all with minimal side effects.
In conclusion, this is the first study to focus specifically on the LMT-GSRCC population, uncovering potential biomarkers and drug targets through proteomic analysis. The findings from this study not only provide a foundation for developing novel targeted therapies but also personalized treatment strategies for GSRCC.
Reference
Title of Original Paper: A comprehensive proteomic analysis uncovers novel molecular subtypes of gastric signet ring cell carcinoma: Identification of potential prognostic biomarkers and therapeutic targets
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101717
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