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Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer
Chen, Owen J.1,2; Castellsagué, Ester3,4,5; Moustafa-Kamal, Mohamed1,2; Nadaf, Javad6; Rivera, Barbara7,8,9; Fahiminiya, Somayyeh3,10; Wang, Yilin1,2; Gamache, Isabelle1; Pacifico, Caterina1,11; Jiang, Lai7,12; Carrot-Zhang, Jian3,10; Witkowski, Leora3,4; Berghuis, Albert M.2,13,14; Schönberger, Stefan15; Schneider, Dominik16; Hillmer, Morten17; Bens, Susanne17; Siebert, Reiner17; Stewart, Colin J.R.18; Zhang, Ziguo19; Chao, William C.H.20; Greenwood, Celia M.T.7,12,21; Barford, David19; Tischkowitz, Marc22; Majewski, Jacek3,10; Foulkes, William D.3,4,23,24; Teodoro, Jose G.1,2,14
2022-10-04
Source PublicationCancer research
ISSN1538-7445
Volume82Issue:19Pages:3499-3515
Abstract

CDC20 is a coactivator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole-exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with ovarian germ cell tumors in two families. Functional characterization showed these mutants retain APC/C activation activity but have impaired binding to BUBR1, a component of the SAC. Expression of L151R and N331K variants promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. Generation of mice carrying the N331K variant using CRISPR-Cas9 showed that, although homozygous N331K mice were nonviable, heterozygotes displayed accelerated oncogenicity of Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor-promoting genes. SIGNIFICANCE: Two germline CDC20 missense variants that segregate with cancer in two families compromise the spindle assembly checkpoint and lead to aberrant mitotic progression, which could predispose cells to transformation. See related commentary by Villarroya-Beltri and Malumbres, p. 3432.

DOI10.1158/0008-5472.CAN-21-3956
URLView the original
Language英語English
Scopus ID2-s2.0-85139570709
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Cited Times [WOS]:1   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Affiliation1.McGill University, Montréal, Canada
2.Department of Biochemistry, McGill University, Montréal, Canada
3.Department of Human Genetics, McGill University, Montréal, Canada
4.Division of Medical Genetics and Cancer Axis, Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montréal, Canada
5.Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, Barcelona, L'Hospitalet de Llobregat, Spain
6.McGill University and Génome Québec Innovation Centre, Montréal, Canada
7.Cancer Axis, Lady Davis Institute, Jewish General Hospital, Montréal, Canada
8.Hereditary Cancer Programme, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, Barcelona, L'Hospitalet de Llobregat, Spain
9.Gerald Bronfman Department of Oncology, McGill University, Montréal, Canada
10.Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Canada
11.Department of Biology, McGill University, Montréal, Canada
12.Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montréal, Canada
13.Centre de Recherche en Biologie Structurale, McGill University, Montréal, Canada
14.Department of Microbiology and Immunology, Montréal, Canada
15.Department of Pediatric Hematology and Oncology, Pediatrics III, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
16.Clinic of Pediatrics, Dortmund Municipal Hospital, Dortmund, Germany
17.Institute of Human Genetics, University of Ulm & Ulm University Medical Center, Ulm, Germany
18.Department of Histopathology, King Edward Memorial Hospital, School for Women's and Infants' Health, University of Western Australia, Perth, Australia
19.Institute of Cancer Research, London, United Kingdom
20.Faculty of Health Sciences, University of Macau, China
21.Departments of Oncology and Human Genetics, McGill University, Montréal, Canada
22.Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom
23.Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montréal, Canada
24.Division of Medical Genetics and Cancer Research Program, Research Institute of the McGill University Health Centre, Montréal, Canada
Recommended Citation
GB/T 7714
Chen, Owen J.,Castellsagué, Ester,Moustafa-Kamal, Mohamed,et al. Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer[J]. Cancer research,2022,82(19):3499-3515.
APA Chen, Owen J..,Castellsagué, Ester.,Moustafa-Kamal, Mohamed.,Nadaf, Javad.,Rivera, Barbara.,Fahiminiya, Somayyeh.,Wang, Yilin.,Gamache, Isabelle.,Pacifico, Caterina.,Jiang, Lai.,Carrot-Zhang, Jian.,Witkowski, Leora.,Berghuis, Albert M..,Schönberger, Stefan.,Schneider, Dominik.,Hillmer, Morten.,Bens, Susanne.,Siebert, Reiner.,Stewart, Colin J.R..,...&Teodoro, Jose G..(2022).Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer.Cancer research,82(19),3499-3515.
MLA Chen, Owen J.,et al."Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer".Cancer research 82.19(2022):3499-3515.
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