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

被引:0
|
作者
Kimura, Hirokazu [1 ]
Paranal, Raymond M. [1 ,2 ]
Nanda, Neha [1 ]
Wood, Laura D. [1 ,3 ]
Eshleman, James R. [1 ,3 ,4 ]
Hruban, Ralph H. [1 ,3 ]
Goggins, Michael G. [1 ,3 ]
Klein, Alison P. [1 ,3 ,4 ]
Roberts, Nicholas J. [1 ,3 ]
机构
[1] Johns Hopkins Univ, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Human Genet Predoctoral Training Program, McKusick Nathans Inst Genet Med, Baltimore, MD USA
[3] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA
来源
ELIFE | 2022年 / 11卷
基金
美国国家卫生研究院;
关键词
pancreas; cancer; familial cancer; CDKN2A; variant of uncertain significance; pancreatic ductal adenocarcinoma; Human; GERM-LINE MUTATIONS; PANCREATIC-CANCER; SOMATIC MUTATIONS; RISK; ASSOCIATION; GENES;
D O I
10.7554/eLife.71137; 10.7554/eLife.71137.sa1; 10.7554/eLife.71137.sa2
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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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页数:16
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