The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma

Pancreatic adenosquamous carcinoma (PASC) is an aggressive cancer whose mutational origins are poorly understood. An early study reported high-frequency somatic mutations affecting UPF1, a nonsense-mediated mRNA decay (NMD) factor, in PASC, but subsequent studies did not observe these lesions. The corresponding controversy about whether mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two mutations in human and mouse cells to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, splicing, UPF1 protein, or NMD efficiency. We subsequently discovered that 45% of mutations reportedly present in PASCs are identical to standing genetic variants in the human population, suggesting that they may be non-pathogenic inherited variants rather than pathogenic mutations. Our data suggest that is not a common functional driver of PASC and motivate further attempts to understand the genetic origins of these malignancies.