Identification and Development of Subtypes with Poor Prognosis in Gastric Cancer Based on Both Hypoxia and Immune Cell Infiltration

Abstract

Yao Wang,1,* Jingjing Sun,1,* Yang Yang,1,* Sonia Zebaze Dongmo,2 Yeben Qian,1 Zhen Wang3 1Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Neurosurgery, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 3Department of General Surgery, Feixi County People’s Hospital, Hefei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yeben QianDepartment of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People’s Republic of ChinaEmail [email protected] WangDepartment of General Surgery, Feixi County People’s Hospital, Hefei, 231200, People’s Republic of ChinaEmail [email protected]: Hypoxia and immune cell infiltration play an important role in the progression and metastasis of gastric cancer. However, the molecular classification of gastric cancer combined with hypoxia and immune cell infiltration remains unknown.Materials and Methods: ssGSEA was used to evaluate the hypoxic state and immune cell infiltration of 1059 gastric cancer samples collected from the GEO and TCGA database. Based on the results, unsupervised clustering was performed to obtain different gastric cancer subtypes. The differentially expressed genes related to OS between these subtypes were utilized for LASSO analysis to construct a prognostic signature (HIscore). Subsequently, small-molecule drugs were predicted using the Connectivity Map (CMAP) database.Results: We obtained three hypoxic-immune infiltration patterns (HIcluster A-C) with different prognoses and classified them as low hypoxic/low immune, high hypoxic/high immune, and low hypoxic/high immune subtypes. Based on the differential genes between HIclusters, we have also obtained other three gastric cancer subtypes (genecluster A-C) and a 13-gene signature (HIscore). At the same time, we extensively explored the clinical and transcriptome traits in different clusters and groups with high or low HIscore. We proved that HIscore is an independent prognostic biomarker and an indicator of genome stability and EMT. Using the CMAP database, we found 96 small-molecule drugs that could reverse the poor prognosis and could serve as therapeutic drugs, especially for gastric cancer patients with high HIscore.Conclusion: Our study evaluated the hypoxic state and immune cell infiltration in gastric tumors, and identified different gastric cancer subtypes. In addition, we established a hypoxia-immune signature to predict prognosis which is tightly linked to tumor EMT and genomic stability. Based on HIscore, we used the CMAP database to explore small-molecule drugs that may have the potential in serving as therapeutic drugs.Keywords: hypoxia, tumor microenvironment, genome instability, microsatellites, mutation burden

Keywords

• hypoxia
• tumor microenvironment
• genome instability
• microsatellites
• mutation burden