The origins and consequences of <i>UPF1</i> variants in pancreatic adenosquamous carcinoma.

Abstract

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 <i>UPF1</i> mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two <i>UPF1</i> mutations in human and mouse cells to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, <i>UPF1</i> splicing, UPF1 protein, or NMD efficiency. We subsequently discovered that 45% of <i>UPF1</i> 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 <i>UPF1</i> is not a common functional driver of PASC and motivate further attempts to understand the genetic origins of these malignancies.