TGFB2 Expression and Methylation Predict Overall Survival in Pancreatic Ductal Adenocarcinoma Patients

Transforming growth factor-beta (TGF-β) exhibits dual roles in pancreatic ductal adenocarcinoma (PDAC), acting as a tumor suppressor in early stages and a tumor promoter in later disease. Among the three isoforms, TGFB2 is particularly associated with poor prognosis and aggressive phenotypes. This study evaluated the prognostic significance of TGFB2 mRNA and methylation levels in PDAC, with an emphasis on age-dependent effects. Bioinformatic analyses revealed that high TGFB2 expression was significantly associated with reduced overall survival (OS) in patients under 65 (TGFB2 high vs. low median OS: 17.9 vs. 66.9 months) but not in older cohorts. IL6 expression, a downstream target of TGF-β, followed a similar survival profile. Moreover, elevated TGFB2 methylation showed improved survival in younger patients (high methylation vs. low methylation median OS: 66.9 vs. 17.9 months). In addition, our clinical data from a PDAC trial using OT-101, an antisense oligonucleotide targeting TGFB2, further supported these findings-young patients treated with OT-101 showed improved OS compared to untreated controls. Notably, the methylation of TGFB1 also correlated with better OS in young patients. These results demonstrate the importance of TGFB2 as both a prognostic biomarker and therapeutic target in younger PDAC patients and further suggest that epigenetic modulation plays a key role in TGF-β signaling in pancreatic cancer progression. Our study emphasizes the isoform- and age-specific prognostic significance of TGFB2 in PDAC and supports the potential insights provided through methylation and expression profiling for personalized treatment strategies, particularly for younger patients who may benefit most from TGFB2-targeted therapies.