Comprehensive Characterization of RNA Processing Factors in Gastric Cancer Identifies a Prognostic Signature for Predicting Clinical Outcomes and Therapeutic Responses

Abstract

RNA processing converts primary transcript RNA into mature RNA. Altered RNA processing drives tumor initiation and maintenance, and may generate novel therapeutic opportunities. However, the role of RNA processing factors in gastric cancer (GC) has not been clearly elucidated. This study presents a comprehensive analysis exploring the clinical, molecular, immune, and drug response features underlying the RNA processing factors in GC. This study included 1079 GC cases from The Cancer Genome Atlas (TCGA, training set), our hospital cohort, and two other external validation sets (GSE15459, GSE62254). We developed an RNA processing-related prognostic signature using Cox regression with the least absolute shrinkage and selection operator (LASSO) penalty. The prognostic value of the signature was evaluated using a multiple-method approach. The genetic variants, pathway activation, immune heterogeneity, drug response, and splicing features associated with the risk signature were explored using bioinformatics methods. Among the tested 819 RNA processing genes, we identified five distinct RNA processing patterns with specific clinical outcomes and biological features. A 10-gene RNA processing-related prognostic signature, involving ZBTB7A, METTL2B, CACTIN, TRUB2, POLDIP3, TSEN54, SUGP1, RBMS1, TGFB1, and PWP2, was further identified. The signature was a powerful and robust prognosis factor in both the training and validation datasets. Notably, it could stratify the survival of patients with GC in specific tumor-node-metastasis (TNM) classification subgroups. We constructed a composite prognostic nomogram to facilitate clinical practice by integrating this signature with other clinical variables (TNM stage, age). Patients with low-risk scores were characterized with good clinical outcomes, proliferation, and metabolism hallmarks. Conversely, poor clinical outcome, invasion, and metastasis hallmarks were enriched in the high-risk group. The RNA processing signature was also involved in tumor microenvironment reprogramming and regulating alternative splicing, causing different drug response features between the two risk groups. The low-risk subgroup was characterized by high genomic instability, high alternative splicing and might benefit from the immunotherapy. Our findings highlight the prognostic value of RNA processing factors for patients with GC and provide insights into the specific clinical and molecular features underlying the RNA processing-related signature, which may be important for patient management and targeting treatment.

Keywords: RNA processing factors; alternative splicing event; drug response; gastric cancer; immune heterogeneity; prognostic model.