The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma
- Fred Hutchinson Cancer Research Center, United States
- University of Washington, United States
- Memorial Sloan Kettering Cancer Center, United States
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 UPF1 mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two UPF1 mutations in human and mouse cells to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, UPF1 splicing, UPF1 protein, or NMD efficiency. We subsequently discovered that 45% of UPF1 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 UPF1 is not a common functional driver of PASC and motivate further attempts to understand the genetic origins of these malignancies.
Data availability
RNA-seq data generated as part of this study have been deposited in the Gene Expression Omnibus (accession number GSE163517). All original gel images are provided.
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The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinomaGene Expression Omnibus, GSE163517.
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pancreatic ductal adenocarcinoma and panreatic adenosquamous carcinoma sequencingNCBI Sequence Read Archive, SRP107982.
Article and author information
Author details
Funding
National Cancer Institute (T32 CA009657)
- Jacob T Polaski
National Institute for General Medical Sciences (T32 GM007270)
- Dylan B Udy
National Cancer Institute (T32 CA160001)
- Ram Kannan
National Cancer Institute (R01 CA204228)
- Steven D D Leach
Leukemia & Lymphoma Society (1344-18)
- Robert K Bradley
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal studies were performed in accordance with institutional and national animal regulations. Animal protocols were approved by the Memorial Sloan-Kettering Cancer Center Institutional Animal Care and Use Committee (14-08-009 and 11-12-029).
Copyright
© 2021, Polaski et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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