Cancer-Testis Antigens as Clinical and Prognostic Biomarkers in Gastric Adenocarcinoma: Integration of Differential Expression, Clinical Associations, Survival, and Co-Expression Networks

Gastric adenocarcinoma (GAC) remains one of the leading causes of cancer-related mortality, characterized by marked molecular and clinical heterogeneity, which underscores the need for robust biomarkers. In this study, we aimed to evaluate the role of cancer-testis antigens (CTAs) in GAC through integrated analyses of differential expression, clinical associations, survival impact, and gene co-expression networks. The cohort included 156 patients with complete clinical data, comprising a total of 362 tissue samples (tumor, peritumoral, and metaplastic). We identified 541 differentially expressed genes, of which 49 corresponded to previously described CTAs. Between GAC and peritumoral tissues, 14 CTAs exhibited significant differential expression, with MAGEA3, MAGEA6, GOLGA6L1, and MAGEA2 among the most highly expressed in tumors. Relevant associations were observed between the expression of MAGEA3, MAGEA6, POTEF, and CTCFL with TNM staging, as well as IGF2BP1, DAZ1/3/4, YBX2, and PCDHA4 in relation to variables such as tumor depth, metastasis, and TCGA subtypes. Survival analysis demonstrated that high expression of IGF2BP1, CTCFL, CT45A5, and LIN28B was strongly associated with worse prognosis (HR > 2.7), whereas SYCE1L, PIK3R3, and ZNF683 showed a protective effect. The co-expression network revealed five main clusters, highlighting germline-related modules (MAGEA, DAZ, CSAG), adhesion and transcriptional regulation (YBX2, POTEF, PCDHA, TAF1L), and immune-related genes (IRAK3, CXCR1, PIK3R3), evidencing functional integration between proliferation, adhesion, and immune microenvironment modulation. Collectively, these findings reinforce CTAs as potential clinical and prognostic biomarkers in GAC, with direct implications for risk stratification and the development of personalized therapeutic strategies.