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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...

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Autores principales: Polaski, Jacob T, Udy, Dylan B, Escobar-Hoyos, Luisa F, Askan, Gokce, Leach, Steven D, Ventura, Andrea, Kannan, Ram, Bradley, Robert K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
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.
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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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