PBRM1 presents a potential prognostic marker and therapeutic target in duodenal papillary carcinoma.

Abstract

BackgroundDue to its rarity, duodenal papillary carcinoma (DPC) is seldom studied as a unique disease and no specific molecular features or treatment guidelines are provided.MethodsWhole‐exome sequencing was performed to gain new insights into the DPC mutation landscape and to identify potential signalling pathways and therapeutic targets. Mechanistically, immunohistochemistry (IHC), immunofluorescence, RNA‐seq, ATAC‐seq and in vitro cell function experiments were performed to confirm the underlying mechanisms.ResultsWe described the mutational landscape of DPC for the first time as a group of rare tumours with a high frequency of dysregulation in the chromatin remodelling pathway, particularly PBRM1‐inactivating mutations that are significantly higher than duodenal adenocarcinomas and ampullary adenocarcinoma (27% vs. 0% vs. 7%, p < .01). In vitro cell experiments showed that downregulation of PBRM1 expression could significantly promote the cancer progression and epithelial‐to‐mesenchymal transition via the PBRM1‐c‐JUN‐VIM axis. The IHC data indicated that PBRM1 deficiency (p = .047) and c‐JUN expression (p < .001) were significantly associated with poor prognosis. Meanwhile, the downregulation of PBRM1 expression in HUTU‐80 cells was sensitive to radiation, which may be due to the suppression of c‐JUN by irradiation.ConclusionsOur findings define a novel molecular subgroup of PBRM1‐inactivating mutations in DPC. PBRM1 play an important role in DPC progression and may serve as a potential therapeutic target and prognostic indicator.