The origins and consequences ofUPF1variants in pancreatic adenosquamous carcinoma

ABSTRACT 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 in UPF1 , 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 whether UPF1 mutations are important contributors to PASC has been exacerbated by a paucity of functional studies of these lesions. Here, we systematically assessed the potential roles of UPF1 mutations in PASC. We modeled two reported UPF1 mutations to find no consistent effects on pancreatic cancer growth, acquisition of adenosquamous features, UPF1 splicing, UPF1 protein levels, or NMD efficiency. We subsequently discovered that ~40% of UPF1 mutations 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 that UPF1 is not a common functional driver of PASC and motivate further attempts to identify unique genetic features defining these malignancies.