Abstract 7643: Prognostic significance and immune infiltration patterns related to Claudin heterogeneity in pancreatic ductal adenocarcinoma patients
Authors: Ajaz A. Bhat, Shahabuddin Usmani, Hana Q. Sadida, Sheema Hashem, Tariq Masoodi, Ikhlak Ahmed, Rakesh Kumar, Mayank Singh, Punita Dhawan, Shahab Uddin, Muzafar A. Macha, Ammira S. Al-Shabeeb Akil
Journal: Cancer Research (2024)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) stands out for its aggressive nature, often manifesting through invasion, metastasis, and recurrence. These characteristics are partly attributable to the Epithelial-mesenchymal transition (EMT), a critical phenomenon that follows the disintegration of epithelial barriers, including tight junctions (TJs), where Claudin (CLDN) proteins are integral components. Objective: This study focused on elucidating the differential expression of claudins in PDAC and exploring their correlations with disease progression, invasiveness, and immune infiltration. Methodology: Utilizing UCSC TOIL RNA-seq, TCGA-PAAD genomic, and clinical data, we investigated the genomic alterations and differential expression of claudins in PDAC. Conducted survival analysis using log-rank tests. Assessed immune infiltration patterns using the EPIC deconvolution algorithm. Results: Of 177 PDAC samples examined, 23 (13%) exhibited at least one form of claudin gene alteration, including mutations, amplifications, or deep deletions. Remarkably, 10 claudins (CLDN1, 2, 4, 5, 7, 11, 12, 15, 18, and 23) were found to be significantly overexpressed in PDAC samples, meeting a log2FC threshold of ≥1 (p &amp;lt; 0.05). Further, we identified a direct correlation between mRNA expression and copy numbers, alongside an inverse relationship with methylation levels, particularly in CLDN1, CLDN12, CLDN15, CLDN23, and CLDN4. Intriguingly, claudin expression escalated from grades G1 to G3 but diminished in G4, with CLDN1, CLDN4, and CLDN7 showing significant variability (Kruskal-Wallis rank test p-values of 1.2E-5, 0.00064, and 0.023, respectively). Survival analysis indicated that high expression levels of CLDN1 and CLDN4 were linked to poorer patient outcomes, while higher levels of CLDN5 and CLDN15 correlated with improved survival (log-rank p-values of 0.007, 0.016, 0.0035, and 0.0012, respectively), findings consistent across both univariate and multivariate analyses. Furthermore, immune infiltration patterns, assessed via the EPIC deconvolution algorithm, varied significantly between high and low CLDN expression groups. Specifically, low CLDN1 expression was associated with increased presence of B-cells, CAF, and CD8+ T-cells but fewer endothelial cells, a pattern reversed in high CLDN1 expression cases. A similar trend was observed for CLDN4. Conclusion: Our study underscores the significant prognostic value of claudin proteins in PDAC, highlighting their potential as indicators of disease progression and survival and their influence on the tumor's immune environment. Citation Format: Ajaz A. Bhat, Shahabuddin Usmani, Hana Q. Sadida, Sheema Hashem, Tariq Masoodi, Ikhlak Ahmed, Rakesh Kumar, Mayank Singh, Punita Dhawan, Shahab Uddin, Muzafar A. Macha, Ammira S. Al-Shabeeb Akil. Prognostic significance and immune infiltration patterns related to Claudin heterogeneity in pancreatic ductal adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7643.