The origins and consequences ofUPF1variants in pancreatic adenosquamous carcinoma

Pancreatic adenosquamous carcinoma (PASC) is a rare and aggressive subtype of pancreatic cancer whose mutational origins are poorly understood. An early study reported somatic mutations inUPF1, which encodes a core component of the nonsense-mediated mRNA decay (NMD) pathway, as a common signature of PASC, but subsequent studies did not observe these lesions in other PASC cohorts. The corresponding controversy about whetherUPF1mutations are important contributors to PASC has been exacerbated by a paucity of functional studies of these lesions. Here, we systematically assessed the potential roles ofUPF1mutations in PASC. We modeled two reportedUPF1mutations to find no consistent effects on pancreatic cancer growth, acquisition of adenosquamous features,UPF1splicing, UPF1 protein levels, or NMD efficiency. We subsequently discovered that ~40% ofUPF1mutations reportedly present in PASCs are identical to standing genetic variation in the human population, suggesting that they are likely non-pathogenic inherited variation rather than pathogenic mutations. Our data suggest thatUPF1is not a common functional driver of PASC and motivate further attempts to identify unique genetic features defining these malignancies.