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.
引用
收藏
页数:16
相关论文
共 50 条
  • [1] The functional role of inherited CDKN2A variants in childhood acute lymphoblastic leukemia
    Li, Chunjie
    Zhao, Xinying
    He, Yingyi
    Li, Ziping
    Qian, Jiabi
    Zhang, Li
    Ye, Qian
    Qiu, Fei
    Lian, Peng
    Qian, Maoxiang
    Zhang, Hui
    PHARMACOGENETICS AND GENOMICS, 2022, 32 (02): : 43 - 50
  • [2] Functional analysis of CDKN2A 5'UTR variants associated with family history of melanoma
    Bisio, A.
    Nasti, S.
    Gargiulo, S.
    Provenzani, A.
    Quattrone, A.
    Inga, A.
    Bianchi-Scarra, G.
    EJC SUPPLEMENTS, 2008, 6 (09): : 124 - 124
  • [3] CDKN2A intronic variants in melanoma identified using Trangenomic WAVE technology: potential significance
    Gardner, JM
    Bowers, R
    Geula, F
    Ivanovich, J
    Cornelius, LA
    Bowcock, AM
    JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2005, 124 (04) : A149 - A149
  • [4] CDKN2A Unclassified Variants in Familial Malignant Melanoma: Combining Functional and Computational Approaches for Their Assessment
    Scaini, Maria Chiara
    Minervini, Giovanni
    Elefanti, Lisa
    Ghiorzo, Paola
    Pastorino, Lorenza
    Tognazzo, Silvia
    Agata, Simona
    Quaggio, Monica
    Zullato, Daniela
    Bianchi-Scarra, Giovanna
    Montagna, Marco
    D'Andrea, Emma
    Menin, Chiara
    Tosatto, Silvio C. E.
    HUMAN MUTATION, 2014, 35 (07) : 828 - 840
  • [5] The functional impact of variants of uncertain significance in BRCA2
    Mesman, Romy L. S.
    Calleja, Fabienne M. G. R.
    Hendriks, Giel
    Morolli, Bruno
    Misovic, Branislav
    Devilee, Peter
    van Asperen, Christi J.
    Vrieling, Harry
    Vreeswijk, Maaike P. G.
    GENETICS IN MEDICINE, 2019, 21 (02) : 293 - 302
  • [6] Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C
    Hu, Chunling
    Nagaraj, Anil Belur
    Shimelis, Hermela
    Montalban, Gemma
    Lee, Kun Y.
    Huang, Huaizhi
    Lumby, Carolyn A.
    Na, Jie
    Susswein, Lisa R.
    Roberts, Maegan E.
    Marshall, Megan L.
    Hiraki, Susan
    LaDuca, Holly
    Chao, Elizabeth
    Yussuf, Amal
    Pesaran, Tina
    Neuhausen, Susan L.
    Haiman, Christopher A.
    Kraft, Peter
    Lindstrom, Sara
    Palmer, Julie R.
    Teras, Lauren R.
    Vachon, Celine M.
    Yao, Song
    Ong, Irene
    Nathanson, Katherine L.
    Weitzel, Jeffrey N.
    Boddicker, Nicholas
    Gnanaolivu, Rohan
    Polley, Eric C.
    Mer, Georges
    Cui, Gaofeng
    Karam, Rachid
    Richardson, Marcy E.
    Domchek, Susan M.
    Yadav, Siddhartha
    Hruska, Kathleen S.
    Dolinsky, Jill
    Weroha, S. John
    Hart, Steven N.
    Simard, Jacques
    Masson, Jean Yves
    Pang, Yuan-Ping
    Couch, Fergus J.
    CANCER RESEARCH, 2023, 83 (15) : 2557 - 2571
  • [7] Functional assays for classification of BRCA2 variants of uncertain significance
    Farrugia, Daniel J.
    Agarwal, Mukesh K.
    Pankratz, Vernon S.
    Deffenbaugh, Amie M.
    Pruss, Dmitry
    Frye, Cynthia
    Wadum, Linda
    Johnson, Kiley
    Mentlick, Jennifer
    Tavtigian, Sean V.
    Goldgar, David E.
    Couch, Fergus J.
    CANCER RESEARCH, 2008, 68 (09) : 3523 - 3531
  • [8] Functional Assays for Analysis of Variants of Uncertain Significance in BRCA2
    Guidugli, Lucia
    Carreira, Aura
    Caputo, Sandrine M.
    Ehlen, Asa
    Galli, Alvaro
    Monteiro, Alvaro N. A.
    Neuhausen, Susan L.
    Hansen, Thomas V. O.
    Couch, Fergus J.
    Vreeswijk, Maaike P. G.
    HUMAN MUTATION, 2014, 35 (02) : 151 - 164
  • [9] Functional characterization of 84 PALB2 variants of uncertain significance
    Wiltshire, Timothy
    Ducy, Mandy
    Foo, Tzeh Keong
    Hu, Chunling
    Lee, Kun Y.
    Nagaraj, Anil Belur
    Rodrigue, Amelie
    Gomes, Thiago T.
    Simard, Jacques
    Monteiro, Alvaro N. A.
    Xia, Bing
    Carvalho, Marcelo A.
    Masson, Jean-Yves
    Couch, Fergus J.
    GENETICS IN MEDICINE, 2020, 22 (03) : 622 - 632
  • [10] A functional assay for the clinical annotation of genetic variants of uncertain significance in Diamond-Blackfan anemia
    Aspesi, Anna
    Betti, Marta
    Sculco, Marika
    Actis, Chiara
    Olgasi, Cristina
    Wlodarski, Marcin W.
    Vlachos, Adrianna
    Lipton, Jeffrey M.
    Ramenghi, Ugo
    Santoro, Claudio
    Follenzi, Antonia
    Ellis, Steven R.
    Dianzani, Irma
    HUMAN MUTATION, 2018, 39 (08) : 1102 - 1111