The UPF1 RNA surveillance gene is commonly mutated in pancreatic adenosquamous carcinoma

Pancreatic adenosquamous carcinomas are rare but highly aggressive tumors, and our understanding of them is limited. In a new study, Miles Wilkinson and colleagues now report that they have identified somatic mutations in an RNA helicase encoded by UPF1 in some pancreatic adenosquamous carcinomas. UPF1 is required for nonsense-mediated RNA decay, suggesting that the aberrant accumulation of altered RNA transcripts may contribute to the malignant phenotype of these tumors and could be a target of diagnostic and therapeutic approaches for this tumor type. Pancreatic adenosquamous carcinoma (ASC) is an enigmatic and aggressive tumor that has a worse prognosis and higher metastatic potential than its adenocarcinoma counterpart. Here we report that ASC tumors frequently harbor somatically acquired mutations in the UPF1 gene, which encodes the core component of the nonsense-mediated RNA decay (NMD) pathway. These tumor-specific mutations alter UPF1 RNA splicing and perturb NMD, leading to upregulated levels of NMD substrate mRNAs. UPF1 mutations are, to our knowledge, the first known unique molecular signatures of pancreatic ASC.