Liang Gu

G2/M checkpoint and P53 pathway are essential in regulating the cell cycle and proliferation of cells, which is related to the progress of tumors. Here, we carried out an integrative analysis of the prognostic genes of these pathways in gastric cancer (GC) and thus developed a molecular subtype. We identified prognostic differential expression genes (PDEGs) of G2/M checkpoint and P53 pathways between normal and tumor tissue in TCGA-STAD and developed a molecular subtype based on PDEGs. Meanwhile, the clinical significance of the molecular subtype was further explored. In addition, a comprehensive model and nomogram based on PDEGs score were constructed and validated by GSE26901 and GSE13861. Gastric cancer cell lines and patients’ specimens were used to validate the expression of selected genes.19 PDEGs were identified from these pathways in TCGA-STAD. Ulteriorly, a PDEGs score model consisting of 4 genes (PVT1, F2R, INCENP, IRAK1) was generated to classify patients into high- and low- PDEGs score subgroups. Patients in low PDEGs score groups had a better prognosis and a higher tumor mutational burden and may be more sensitive to chemotherapy and immunotherapy. Notably, the combination of PDEGs score and clinical features showed a pleasing survival prediction ability. In the GSE13861 cohort, the PDEGs score and its derivative model were confirmed with significant predictive effects in overall survival. Furthermore, these genes were significantly upregulated in both GC cell lines and tumor tissues and F2R was the hub gene resulting in poor survival. This paper has provided a distinct insight for tumor classification predicting prognosis more accurately and having the potential to instruct the use of chemotherapy and immunotherapy for patients with GC.

Background: Surgical treatment has been widely controversial for gastric cancer accompanied by liver metastasis (GCLM). This paper aims to develop and validate a nomogram to predict the survival and estimate surgical benefits for GCLM patients.Methods: A total of 616 GCLM patients from the Surveillance, Epidemiology, and End Results Program (SEER) database and 74 GCLM patients receiving primary tumor resection (PTR) from the Chinese center were included in this study. Patients from the SEER database were divided into training set (with PTR) (n=493) and non-operative set (without PTR) (n=123). Patients undergoing PTR from China were included as external validation set. Independent risk factors associated with the overall survival of GCLM patients undergoing PTR were identified in the training set via log-rank test and Cox regression analysis. Afterwards, a comprehensive model and corresponding nomogram were constructed and validated by validation set.Results: The survival of patients undergoing PTR (n=493) was longer than that without PTR (n=123) (log-rank test, pp=0.25).Conclusions: The nomogram could predict survival of GCLM patients receiving PTR with acceptable accuracy. In addition, although PTR did improve the survival of whole GCLM patients, patients in the high-risk subgroup were unable to benefit from PTR, which could assist clinicians to make decisions for the treatment of GCLM.

Background: Tumor-associated macrophages (TAMs) have been demonstrated to be associated with tumor progression. However, the different subpopulations of TAMs and their roles in gastric cancer (GC) remain poorly understood. This study aims to assess the effects of Spi-1 proto-oncogene (SPI1)⁺CD68⁺ TAMs in GC. Methods: The distribution of SPI1⁺CD68⁺ TAMs in GC tissue was estimated by immunohistochemistry, immunofluorescence, and flow cytometry. Single-cell transcriptome analysis and multiplex fluorescence immunohistochemistry were applied to explore the role of SPI1⁺CD68⁺ TAMs in an immune contexture. SPI1 overexpression or knockdown cells were constructed to evaluate its role in macrophage polarization and angiogenesis in vitro and in vivo. Chromatin immunoprecipitation was used to verify the mechanism of SPI1 transcriptional function. The effect of combined antiangiogenic and immunotherapy was further validated using mouse peritoneal metastasis models. Results: Single-cell transcriptome analysis and immunohistochemistry demonstrated that SPI1 was expressed in macrophages, with a higher enrichment in metastatic lesions than in primary tumors. Higher SPI1⁺CD68⁺ TAMs infiltration was associated with poor overall survival. Mechanically, SPI1 promoted the M2-type macrophage polarization. SPI1 could bind to the promoter of vascular endothelial growth factor A and facilitate angiogenesis. Moreover, the level of SPI1⁺CD68⁺ TAMs infiltration was closely related to the efficacy of immunotherapy, especially when combined with antiangiogenic therapy. Conclusions: The present study showed that SPI1⁺CD68⁺ TAMs are a promising biomarker for predicting prognosis, antiangiogenic drug sensitivity, and combination target of immunotherapy in patients with GC.