DNMT3A p.R882C driven proliferation and anti-apoptotic effects in pancreatic cancer cells.

Pancreatic cancer, one of the most lethal malignancies, is characterized by insidious onset, frequent late-stage diagnosis, rapid progression, and limited surgical opportunities. Pancreatic ductal adenocarcinoma (PDAC), accounting for over 90% of pancreatic cancer cases, remains a therapeutic challenge due to the scarcity of effective targeted therapies. In this study, we collected formalin-fixed paraffin-embedded (FFPE) specimens from three patients with moderately to poorly differentiated PDAC, extracted genomic DNA, and performed whole-exome sequencing. Through bioinformatics analysis, we identified 68 high-risk deleterious variants, including the DNMT3A p.R882C mutation. This mutation exhibits low frequency in public databases (e.g., esp6500si, GnomAD) and is consistently predicted as deleterious by multiple algorithms (SIFT, Polyphen, LRT, CADD). To investigate its functional impact, wild-type and mutant DNMT3A constructs were cloned into p3xflag-CMV-10 plasmids and transfected into the pancreatic cancer cell lines PANC-1 and PaTu 8988t. In vitro cellular experiments demonstrated that the DNMT3A p.R882C mutation does not alter DNMT3A expression at mRNA or protein levels but significantly promotes cancer cell proliferation and migration while inhibiting apoptosis. These findings suggest that the DNMT3A p.R882C mutation may play a critical role in PDAC pathogenesis. This study not only provides essential laboratory evidence for elucidating PDAC development but also offers new insights for potential targeted therapeutic strategies in pancreatic cancer.