Cancer-testis antigens in gastric adenocarcinoma: Integration of differential expression, clinical associations, survival, and co-expression networks

Abstract

Gastric adenocarcinoma (GAC) remains one of the deadliest malignancies worldwide, and the identification of molecular biomarkers is essential to improve prognostic stratification and guide therapeutic strategies. Cancer-testis antigens (CTAs) represent promising targets for immunotherapy, yet their expression landscape in GAC remains limited, especially when considering comprehensive and updated gene lists. In this study, we analyzed 389 samples, including tumor, peritumoral, metaplastic, and normal tissues, using RNA sequencing data to characterize the transcriptional profile of CTAs in GAC. We identified 104 CTAs differentially expressed among groups, with a predominance of upregulated genes in tumors compared with other tissues. The expression of several CTAs, such as MAGEA2, MAGEA3, MAGEA6, MAGEA12, CTCFL, IGF2BP1, and GAST, showed significant associations with clinically relevant variables, including tumor-node-metastasis staging, lymph node involvement, metastasis, histological subtype, and therapeutic management. Survival analysis revealed 17 CTA genes associated with overall survival, of which 14 correlated with poor prognosis, whereas PIK3R3, SYCE1L, and ZNF683 demonstrated a protective effect. Co-expression analysis identified five well-defined functional modules, reflecting coordinated CTA signatures related to germline reprogramming, proliferation, and immune remodeling within the tumor microenvironment. Collectively, our results provide the most comprehensive characterization of CTAs in GAC to date, highlighting genes with clinical relevance, prognostic value, and translational potential as candidates for future personalized immunotherapeutic approaches.

Keywords

Antigens / Cancer-testis antigens / Gastric cancer / Molecular biomarkers / Therapeutic targets / Transcriptomics

Acknowledgments

The authors thank the Núcleo de Pesquisas em Oncologia at the Universidade Federal do Pará (UFPA) for the technical support, infrastructure, and resources provided for the development of this study.

Funding

This research was funded by the Coordenação deAperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil (Funding Code 001), and by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (385189/2025-7), through the awarding of scholarships.

Conflict of interest

The authors declare that this research was conducted without any commercial or financial relationships that could be interpreted as potential conflicts of interest.

Author contributions

Conceptualization: Jade Dias Valente, Livia Érika Carlos Marques, André Salim Khayat, Paulo Pimentel de Assumpção, Rommel Mario Rodríguez Burbano

Data curation: Jade Dias Valente, Ronald Matheus da Silva Mourão, Fabiano Cordeiro Moreira, Bianca de Fátima dos Reis Rodrigues, Jéssica Manoelli Costa da Silva

Formal analysis: Jade Dias Valente, Ronald Matheus da Silva Mourão, Fabiano Cordeiro Moreira

Funding acquisition: Livia Érika Carlos Marques, Samia Demachki, Samir Mansour Moraes Casseb, Geraldo Ishak, Paulo Pimentel de Assumpção, Rommel Mario Rodríguez Burbano

Investigation: Jade Dias Valente, Livia Érika Carlos Marques, Ronald Matheus da Silva Mourão, Fabiano Cordeiro Moreira, Bianca de Fátima dos Reis Rodrigues, Louise Sousa de Souza, Jéssica Manoelli Costa da Silva, Samir Mansour Moraes Moraes Casseb, Geraldo Ishak

Methodology: Jade Dias Valente, Livia Érika Carlos Marques, Ronald Matheus da Silva Mourão, Fabiano Cordeiro Moreira, Jéssica Manoelli Costa da Silva, Samir Mansour Moraes Casseb

Project administration: Livia Érika Carlos Marques, Paulo Pimentel de Assumpção, Rommel Mario Rodríguez Burbano

Resources: Livia Érika Carlos Marques, Samir Mansour Moraes Moraes Casseb, André Salim Khayat, Samia Demachki, Geraldo Ishak, Fabiano Cordeiro Moreira, Mario Rodriguez Burbano, Paulo Pimentel de Assumpção

Supervision: Livia Érika Carlos Marques, Paulo Pimentel de Assumpção, Rommel Mario Rodríguez Burbano

Visualization: Jade Dias Valente, Livia Érika Carlos Marques, Ronald Matheus da Silva Mourão, Fabiano Cordeiro Moreira

Writing-original draft: Jade Dias Valente, Bianca de Fátima dos Reis Rodrigues, Louise Sousa de Souza

Writing-review & editing: All authors

Ethics approval and consent to participate

This study was approved by the Research Ethics Committee of the Núcleo de Pesquisas em Oncologia (Approval No. 47580121.9.0000.5634), which authorized the analyses and procedures described. The committee specifically approved the collection of biological samples and the review of medical records. As the study involved human subjects, all relevant ethical procedures were followed. All participants provided written informed consent, agreeing to take part in the research in accordance with current ethical guidelines.

Consent for publication

All participants included in this study provided written informed consent for the publication of their research data. The study did not involve the publication of participant images. In addition, no individually identifiable information was disclosed, and all sensitive data were appropriately withheld to ensure confidentiality.

Availability of data

The data generated and analyzed in this study include sensitive clinical information derived from patient medical records and biological samples, which are subject to restrictions imposed by the Research Ethics Committee. Therefore, these data cannot be made publicly available. Anonymized data may be provided upon reasonable request to the corresponding author.

Further disclosure

This manuscript was previously deposited as a preprint on the bioRxiv server under the doi: 10.1101/2025.09.17.676427. The content of this submission corresponds to the revised version of the material originally made available in the preprint.

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