1. Cancer Biology
  2. Genetics and Genomics
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Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance

  1. Hirokazu Kimura
  2. Raymond M Paranal
  3. Neha Nanda
  4. Laura D Wood
  5. James R Eshleman
  6. Ralph H Hruban
  7. Michael G Goggins
  8. Alison P Klein
  9. Nicholas Jason Roberts  Is a corresponding author
  1. Johns Hopkins University, United States
  2. The Johns Hopkins University, United States
Research Article
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Cite this article as: eLife 2022;11:e71137 doi: 10.7554/eLife.71137

Abstract

Pathogenic germline CDKN2A variants are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). CDKN2A variants of uncertain significance (VUSs) are reported in up to 4.3% of patients with PDAC and result in significant uncertainty for patients and their family members as an unknown fraction are functionally deleterious, and therefore, likely pathogenic. Functional characterization of CDKN2A VUSs is needed to reclassify variants and inform clinical management. 29 germline CDKN2A VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. 12 of the 29 CDKN2A VUSs were functionally deleterious (11 VUSs) or potentially functionally deleterious (1 VUS) and were reclassified as likely pathogenic variants. Thus, over 40% of CDKN2A VUSs identified in patients with PDAC are functionally deleterious and likely pathogenic. When incorporating VUSs found to be functionally deleterious, and reclassified as likely pathogenic, the prevalence of pathogenic/likely pathogenic CDKN2A in patients with PDAC reported in the published literature is increased to up to 4.1% of patients, depending on family history. Therefore, CDKN2A VUSs may play a significant, unappreciated role in risk of pancreatic cancer. These findings have significant implications for the counselling and care of patients and their relatives.

Data availability

All data generated or analysed during this study are included in the manuscript, supporting files, and as Source data and Source code.

Article and author information

Author details

  1. Hirokazu Kimura

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  2. Raymond M Paranal

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  3. Neha Nanda

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  4. Laura D Wood

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  5. James R Eshleman

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  6. Ralph H Hruban

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    Ralph H Hruban, has the right to receive royalty payments from Thrive Earlier Diagnosis for the GNAS in pancreatic cysts invention in a relationship overseen by Johns Hopkins University..
  7. Michael G Goggins

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  8. Alison P Klein

    Department of Pathology, Johns Hopkins University, Baltimore, United States
    Competing interests
    No competing interests declared.
  9. Nicholas Jason Roberts

    The Johns Hopkins University, Baltimore, United States
    For correspondence
    nrobert8@jhmi.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8709-0664

Funding

The Sol Goldman Pancreatic Cancer Research Center (Pilot Grant)

  • Nicholas Jason Roberts

National Institutes of Health (S10 OD026859)

  • Nicholas Jason Roberts

The Rolfe Pancreatic Cancer Foundation

  • Nicholas Jason Roberts

National Institutes of Health (P50 CA622924)

  • Alison P Klein
  • Nicholas Jason Roberts

The Japanese Society of Gastroenterology

  • Hirokazu Kimura

The Japan Society for Promotion of Science

  • Hirokazu Kimura

The Joseph C Monastra Foundation

  • Nicholas Jason Roberts

The Geral O Mann Foundation

  • Nicholas Jason Roberts

Art Creates Cures Foundation

  • Nicholas Jason Roberts

Susan Wojcicki and Denis Troper

  • Nicholas Jason Roberts

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Emil Lou, University of Minnesota, United States

Publication history

  1. Received: June 9, 2021
  2. Accepted: January 6, 2022
  3. Accepted Manuscript published: January 10, 2022 (version 1)

Copyright

© 2022, Kimura 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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