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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 c...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846273/ https://www.ncbi.nlm.nih.gov/pubmed/33404013 http://dx.doi.org/10.7554/eLife.62209 |
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author | Polaski, Jacob T Udy, Dylan B Escobar-Hoyos, Luisa F Askan, Gokce Leach, Steven D Ventura, Andrea Kannan, Ram Bradley, Robert K |
author_facet | Polaski, Jacob T Udy, Dylan B Escobar-Hoyos, Luisa F Askan, Gokce Leach, Steven D Ventura, Andrea Kannan, Ram Bradley, Robert K |
author_sort | Polaski, Jacob T |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7846273 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-78462732021-02-01 The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma Polaski, Jacob T Udy, Dylan B Escobar-Hoyos, Luisa F Askan, Gokce Leach, Steven D Ventura, Andrea Kannan, Ram Bradley, Robert K eLife Cancer Biology 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. eLife Sciences Publications, Ltd 2021-01-06 /pmc/articles/PMC7846273/ /pubmed/33404013 http://dx.doi.org/10.7554/eLife.62209 Text en © 2021, Polaski et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Polaski, Jacob T Udy, Dylan B Escobar-Hoyos, Luisa F Askan, Gokce Leach, Steven D Ventura, Andrea Kannan, Ram Bradley, Robert K The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma |
title | The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma |
title_full | The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma |
title_fullStr | The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma |
title_full_unstemmed | The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma |
title_short | The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma |
title_sort | origins and consequences of upf1 variants in pancreatic adenosquamous carcinoma |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846273/ https://www.ncbi.nlm.nih.gov/pubmed/33404013 http://dx.doi.org/10.7554/eLife.62209 |
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