1. Cancer Biology
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The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma

  1. Jacob T Polaski
  2. Dylan B Udy
  3. Luisa F Escobar-Hoyos
  4. Gokce Askan
  5. Steven D D Leach
  6. Andrea Ventura
  7. Ram Kannan  Is a corresponding author
  8. Robert K Bradley  Is a corresponding author
  1. Fred Hutchinson Cancer Research Center, United States
  2. University of Washington, United States
  3. Memorial Sloan Kettering Cancer Center, United States
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Cite this article as: eLife 2021;10:e62209 doi: 10.7554/eLife.62209

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.

Article and author information

Author details

  1. Jacob T Polaski

    Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Dylan B Udy

    Molecular & Cellular Biology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Luisa F Escobar-Hoyos

    Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Gokce Askan

    Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Steven D D Leach

    Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Andrea Ventura

    Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ram Kannan

    Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States
    For correspondence
    kannanr@mskcc.org
    Competing interests
    The authors declare that no competing interests exist.
  8. Robert K Bradley

    Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States
    For correspondence
    rbradley@fredhutch.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8046-1063

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).

Reviewing Editor

  1. Eric J Wagner, University of Texas Medical Branch at Galveston, United States

Publication history

  1. Received: August 18, 2020
  2. Accepted: January 5, 2021
  3. Accepted Manuscript published: January 6, 2021 (version 1)

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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