Affiliation:
1. The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University
2. Human Genetics Predoctoral Training Program, the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine
3. Department of Oncology, The Johns Hopkins University School of Medicine
4. Department of Epidemiology, The Johns Hopkins University Bloomberg School of Public Health
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. 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.
Funder
The Sol Goldman Pancreatic Cancer Research Center
The Rolfe Pancreatic Cancer Foundation
National Institutes of Health
The Japanese Society of Gastroenterology
The Japan Society for Promotion of Science
The Joseph C Monastra Foundation
The Geral O Mann Foundation
Art Creates Cures Foundation
Susan Wojcicki and Denis Troper
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
5 articles.
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