Identification of Cuproptosis-Related Subtypes, Establishment of a Prognostic Signature and Characterization of the Tumor Microenvironment in Gastric Cancer

Abstract

Purpose

Cuproptosis is a newly identified form of programmed cell death. We aimed to comprehensively discuss the correlation of cuproptosis with gastric cancer (GC) using bioinformatic methods.

Patients and Methods

This study selected GC bulk and single-cell RNA sequencing profiles from public databases. Based on the enrichment pattern of cuproptosis-related gene sets (CRGSs), GC patients were classified into different cuproptosis subtypes. A series of systematic analyses was performed to investigate the correlation of cuproptosis subtype with biological function and immune cell infiltration. In addition, we established a CRGS risk score signature to quantify GC patients’ risk level, and analyzed the signature’s relationship with clinical features, tumor microenvironment (TME) and treatment responses. Genes used for the construction of the risk score model were also detected in GC tumor and normal tissues by real-time quantitative polymerase chain reaction (RT-qPCR).

Results

First, analysis of scRNA-seq data revealed the alterations in CRGS enrichment scores for patients with GC and precancerous diseases. Then, based on large GC patient cohorts, two cuproptosis subtypes with significant differences in survival, biological function and TME were identified. Furthermore, we established a CRGS risk score signature. High-risk patients on the CRGS risk score signature with worse overall survival were characterized by higher immune and stromal contents in the TME, more advanced clinicopathological features, and better sensitivity to a wider range of anti-tumor drugs. Low-risk patients were correlated with higher tumor purity, and demonstrated more favorable clinical outcomes and higher sensitivity to immunotherapy.

Conclusion

The current work elucidated that cuproptosis plays an important role in the regulation of TME landscapes in GC. Two cuproptosis subtypes with distinct TME characteristics were identified. In addition, the establishment of a CRGS risk score signature could provide novel insights into accurate prediction and personalized treatment for GC patients.

Keywords:

• gastric cancer
• cuproptosis
• single-cell RNA sequencing
• molecular subtype
• prognostic model
• tumor microenvironment

Data Sharing Statement

The datasets supporting the conclusions of this article are available in The Cancer Genome Atlas (https://portal.gdc.cancer.gov) and Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo).

Ethics Approval and Consent to Participate

The study design was in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Renmin Hospital of Wuhan University (No. NCT03972956V1.1), and we have obtained informed consent from the patients for using GC samples (No. SAMPGICU2019-2).

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.