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Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance

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 un...

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Autores principales: Kimura, Hirokazu, Paranal, Raymond M, Nanda, Neha, Wood, Laura D, Eshleman, James R, Hruban, Ralph H, Goggins, Michael G, Klein, Alison P, Roberts, Nicholas J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8824478/
https://www.ncbi.nlm.nih.gov/pubmed/35001868
http://dx.doi.org/10.7554/eLife.71137
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author Kimura, Hirokazu
Paranal, Raymond M
Nanda, Neha
Wood, Laura D
Eshleman, James R
Hruban, Ralph H
Goggins, Michael G
Klein, Alison P
Roberts, Nicholas J
author_facet Kimura, Hirokazu
Paranal, Raymond M
Nanda, Neha
Wood, Laura D
Eshleman, James R
Hruban, Ralph H
Goggins, Michael G
Klein, Alison P
Roberts, Nicholas J
author_sort Kimura, Hirokazu
collection PubMed
description 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. Twenty-nine germline CDKN2A VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. Twelve 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.
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spelling pubmed-88244782022-02-10 Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance Kimura, Hirokazu Paranal, Raymond M Nanda, Neha Wood, Laura D Eshleman, James R Hruban, Ralph H Goggins, Michael G Klein, Alison P Roberts, Nicholas J eLife Cancer Biology 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. Twenty-nine germline CDKN2A VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. Twelve 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. eLife Sciences Publications, Ltd 2022-01-10 /pmc/articles/PMC8824478/ /pubmed/35001868 http://dx.doi.org/10.7554/eLife.71137 Text en © 2022, Kimura et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cancer Biology
Kimura, Hirokazu
Paranal, Raymond M
Nanda, Neha
Wood, Laura D
Eshleman, James R
Hruban, Ralph H
Goggins, Michael G
Klein, Alison P
Roberts, Nicholas J
Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance
title Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance
title_full Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance
title_fullStr Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance
title_full_unstemmed Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance
title_short Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance
title_sort functional cdkn2a assay identifies frequent deleterious alleles misclassified as variants of uncertain significance
topic Cancer Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8824478/
https://www.ncbi.nlm.nih.gov/pubmed/35001868
http://dx.doi.org/10.7554/eLife.71137
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