Soluble CTLA-4 and high-risk genetic variants: A new frontier in pancreatic ductal adenocarcinoma (PDAC) biomarkers

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Hassan M.; Elhusseny Y.; Agamy F.E.; Azmy M.M.; Balata M.

Journal: Biochemistry and Biophysics Reports

Publisher: Elsevier B.V.

Publication Date: December 2025

Volume / Issue: Volume 44

Article No.: 102304

ISSN: 24055808

DOI: 10.1016/j.bbrep.2025.102304

Scopus: View on Scopus

Document Type: Article

Access: All Open Access; Gold Open Access; Green Open Access

Authors and Affiliations

Hassan M., Immunology Department, Theodor Bilharz Research Institute, Giza, Egypt; Elhusseny Y., Medical Biochemistry and Molecular Biology, School of Medicine, NewGiza University, Giza, Egypt; Agamy F.E., Faculty of Medicine, Al-Azhar university, Cairo, Egypt; Azmy M.M., Faculty of Biotechnology, Misr University for Science and Technology, Giza, Egypt; Balata M., University Hospital Rostock, Ernst-Heydemann-Straße 6, Rostock, 18057, Germany, University Hospital Bonn, Venusberg-Campus 1, Bonn, 53127, Germany

Abstract

CTLA-4 is regarded as the “leader” of immune checkpoint inhibitors, as it suppresses autoreactive T cells at the initial phase of naïve T-cell activation. Its genetic variability may impair its effectiveness in the anti-tumor response. Additionally, the presence of soluble CTLA-4 (sCTLA-4) in the tumor microenvironment suppresses effector T-cell activation, allowing for tumor evasion. Therefore, this study aimed to explore the relationship between CTLA-4 polymorphisms and sCTLA-4 and the risk of pancreatic ductal adenocarcinoma (PDAC) in an Egyptian population. Three single-nucleotide polymorphisms of the CTLA-4 gene (rs231726, rs11571317, and rs13384548) were analyzed, and sCTLA-4 levels were assessed in 125 PDAC patients and 125 healthy controls. The rs231726 TT genotype was associated with a six-fold greater risk of PDAC, advanced disease grades, and elevated carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA). Also, the T-allele increased the likelihood of developing PDAC by four times. Conversely, the CC genotype and C-allele conferred protection against PDAC development. The rs11571317 CC genotype and C-allele elevated the PDAC risk by 4.91 and 3.49-fold, respectively, with no relationship to disease severity. The rs13384548 polymorphism showed no significant association with PDAC susceptibility. sCTLA-4 correlated positively with CA19-9 and CEA levels, with the highest levels found in individuals possessing the rs231726 TT genotype and high malignancy grades. These findings highlight the potential of CTLA-4 SNPs and sCTLA-4 as biomarkers for PDAC diagnosis and prognosis. Integrating these biomarkers into screening programs can offer improved strategies for early detection and disease management in high-risk populations. © 2025 The Authors.

Keywords

CTLA-4; Gene polymorphisms; Immune checkpoint; Pancreatic ductal adenocarcinoma; rs11571317; rs231726; CA 19-9 antigen; carcinoembryonic antigen; cytotoxic T lymphocyte antigen 4; adult; allele; antigen blood level; Article; cancer diagnosis; cancer grading; cancer growth; cancer patient; cancer prognosis; cancer risk; cancer screening; cancer susceptibility; cancer therapy; case control study; cohort analysis; controlled study; CTLA 4 gene; disease severity; early diagnosis; Egyptian; female; gene function; genetic association; genetic risk; genetic variability; genotype; high risk patient; human; major clinical study; male; middle aged; pancreatic ductal carcinoma; patient care; risk assessment; single nucleotide polymorphism

Citation Information

Scopus Citations: 2

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