ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk
PURPOSE: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ? 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hamperin...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Recursos: | Servizo Galego de Saúde (SERGAS) |
| Repositorio: | RUNA. Repositorio da Consellería de Sanidade e Sergas |
| OAI Identifier: | oai:runa.sergas.gal:20.500.11940/21475 |
| Acesso em linha: | https://portalcientifico.sergas.gal//documentos/64f6355666ccc641d10d6b7e http://hdl.handle.net/20.500.11940/21475 |
| Access Level: | acceso abierto |
| Palavra-chave: | Humans Female Breast Neoplasms Genetic Predisposition to Disease Checkpoint Kinase 2 Mutation, Missense Germ-Line Mutation Germ Cells FPGMX |
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| dc.title.none.fl_str_mv |
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk |
| title |
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk |
| spellingShingle |
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk Stolarova, L. Humans Female Breast Neoplasms Genetic Predisposition to Disease Checkpoint Kinase 2 Mutation, Missense Germ-Line Mutation Germ Cells FPGMX FPGMX |
| title_short |
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk |
| title_full |
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk |
| title_fullStr |
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk |
| title_full_unstemmed |
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk |
| title_sort |
ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk |
| dc.creator.none.fl_str_mv |
Stolarova, L. Kleiblova, P. Zemankova, P. Stastna, B. Janatova, M. Soukupova, J. Achatz, M.I. Ambrosone, C. Apostolou, P. Arun, B.K. Auer, P. Barnard, M. Bertelsen, B. Blok, M.J. Boddicker, N. Brunet, J. Burnside, E.S. Calvello, M. Campbell, I. Chan, S.H. Chen, F. Chiang, J.B. Coppa, A. Cortesi, L. Crujeiras-González, A. De Leeneer, K. De Putter, R. DePersia, A. Devereux, L. Domchek, S. Efremidis, A. Engel, C. Ernst, C. Evans, D.G.R. Feliubadaló, L. Fostira, F. Fuentes-Ríos, O. Gómez-García, E.B. González, S. Haiman, C. Hansen, T.V.O. Hauke, J. Hodge, J. Hu, C. Huang, H. Ishak, N.D.B. Iwasaki, Y. Konstantopoulou, I. Kraft, P. Lacey, J. Lázaro, C. Li, N. Lim, W.K. Lindstrom, S. Lori, A. Martinez, E. Martins, A. Matsuda, K. Matullo, G. McInerny, S. Michailidou, K. Montagna, M. Monteiro, A.N.A. Mori, L. Nathanson, K. Neuhausen, S.L. Nevanlinna, H. Olson, J.E. Palmer, J. Pasini, B. Patel, A. Piane, M. Poppe, B. Radice, P. Renieri, A. Resta, N. Richardson, M.E. Rosseel, T. Ruddy, K.J. Santamariña Pena, Marta Dos Santos, E.S. Teras, L. Toland, A.E. Trentham-Dietz, A. Vachon, C.M. Volk, A.E. Weber-Lassalle, N. Weitzel, J.N. Wiesmuller, L. Winham, S. Yadav, S. Yannoukakos, D. Yao, S. Zampiga, V. Zethoven, M. Zhang, Z.W. Zima, T. Spurdle, A.B. Vega Gliemmo, Ana Rossing, M. Del Valle, J. De Nicolo, A. Hahnen, E. Claes, K.B.M. Ngeow, J. Momozawa, Y. James, P.A. Couch, F.J. Macurek, L. Kleibl, Z. |
| author |
Stolarova, L. |
| author_facet |
Stolarova, L. Kleiblova, P. Zemankova, P. Stastna, B. Janatova, M. Soukupova, J. Achatz, M.I. Ambrosone, C. Apostolou, P. Arun, B.K. Auer, P. Barnard, M. Bertelsen, B. Blok, M.J. Boddicker, N. Brunet, J. Burnside, E.S. Calvello, M. Campbell, I. Chan, S.H. Chen, F. Chiang, J.B. Coppa, A. Cortesi, L. Crujeiras-González, A. De Leeneer, K. De Putter, R. DePersia, A. Devereux, L. Domchek, S. Efremidis, A. Engel, C. Ernst, C. Evans, D.G.R. Feliubadaló, L. Fostira, F. Fuentes-Ríos, O. Gómez-García, E.B. González, S. Haiman, C. Hansen, T.V.O. Hauke, J. Hodge, J. Hu, C. Huang, H. Ishak, N.D.B. Iwasaki, Y. Konstantopoulou, I. Kraft, P. Lacey, J. Lázaro, C. Li, N. Lim, W.K. Lindstrom, S. Lori, A. Martinez, E. Martins, A. Matsuda, K. Matullo, G. McInerny, S. Michailidou, K. Montagna, M. Monteiro, A.N.A. Mori, L. Nathanson, K. Neuhausen, S.L. Nevanlinna, H. Olson, J.E. Palmer, J. Pasini, B. Patel, A. Piane, M. Poppe, B. Radice, P. Renieri, A. Resta, N. Richardson, M.E. Rosseel, T. Ruddy, K.J. Santamariña Pena, Marta Dos Santos, E.S. Teras, L. Toland, A.E. Trentham-Dietz, A. Vachon, C.M. Volk, A.E. Weber-Lassalle, N. Weitzel, J.N. Wiesmuller, L. Winham, S. Yadav, S. Yannoukakos, D. Yao, S. Zampiga, V. Zethoven, M. Zhang, Z.W. Zima, T. Spurdle, A.B. Vega Gliemmo, Ana Rossing, M. Del Valle, J. De Nicolo, A. Hahnen, E. Claes, K.B.M. Ngeow, J. Momozawa, Y. James, P.A. Couch, F.J. Macurek, L. Kleibl, Z. |
| author_role |
author |
| author2 |
Kleiblova, P. Zemankova, P. Stastna, B. Janatova, M. Soukupova, J. Achatz, M.I. Ambrosone, C. Apostolou, P. Arun, B.K. Auer, P. Barnard, M. Bertelsen, B. Blok, M.J. Boddicker, N. Brunet, J. Burnside, E.S. Calvello, M. Campbell, I. Chan, S.H. Chen, F. Chiang, J.B. Coppa, A. Cortesi, L. Crujeiras-González, A. De Leeneer, K. De Putter, R. DePersia, A. Devereux, L. Domchek, S. Efremidis, A. Engel, C. Ernst, C. Evans, D.G.R. Feliubadaló, L. Fostira, F. Fuentes-Ríos, O. Gómez-García, E.B. González, S. Haiman, C. Hansen, T.V.O. Hauke, J. Hodge, J. Hu, C. Huang, H. Ishak, N.D.B. Iwasaki, Y. Konstantopoulou, I. Kraft, P. Lacey, J. Lázaro, C. Li, N. Lim, W.K. Lindstrom, S. Lori, A. Martinez, E. Martins, A. Matsuda, K. Matullo, G. McInerny, S. Michailidou, K. Montagna, M. Monteiro, A.N.A. Mori, L. Nathanson, K. Neuhausen, S.L. Nevanlinna, H. Olson, J.E. Palmer, J. Pasini, B. Patel, A. Piane, M. Poppe, B. Radice, P. Renieri, A. Resta, N. Richardson, M.E. Rosseel, T. Ruddy, K.J. Santamariña Pena, Marta Dos Santos, E.S. Teras, L. Toland, A.E. Trentham-Dietz, A. Vachon, C.M. Volk, A.E. Weber-Lassalle, N. Weitzel, J.N. Wiesmuller, L. Winham, S. Yadav, S. Yannoukakos, D. Yao, S. Zampiga, V. Zethoven, M. Zhang, Z.W. Zima, T. Spurdle, A.B. Vega Gliemmo, Ana Rossing, M. Del Valle, J. De Nicolo, A. Hahnen, E. Claes, K.B.M. Ngeow, J. Momozawa, Y. James, P.A. Couch, F.J. Macurek, L. Kleibl, Z. |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Humans Female Breast Neoplasms Genetic Predisposition to Disease Checkpoint Kinase 2 Mutation, Missense Germ-Line Mutation Germ Cells FPGMX FPGMX |
| topic |
Humans Female Breast Neoplasms Genetic Predisposition to Disease Checkpoint Kinase 2 Mutation, Missense Germ-Line Mutation Germ Cells FPGMX FPGMX |
| description |
PURPOSE: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ? 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). EXPERIMENTAL DESIGN: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. RESULTS: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results. CONCLUSIONS: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 |
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info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://portalcientifico.sergas.gal//documentos/64f6355666ccc641d10d6b7e http://hdl.handle.net/20.500.11940/21475 |
| url |
https://portalcientifico.sergas.gal//documentos/64f6355666ccc641d10d6b7e http://hdl.handle.net/20.500.11940/21475 |
| dc.language.none.fl_str_mv |
Inglés |
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Inglés |
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http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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reponame:RUNA. Repositorio da Consellería de Sanidade e Sergas instname:Servizo Galego de Saúde (SERGAS) |
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Servizo Galego de Saúde (SERGAS) |
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RUNA. Repositorio da Consellería de Sanidade e Sergas |
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RUNA. Repositorio da Consellería de Sanidade e Sergas |
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1869404224056459264 |
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ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer RiskStolarova, L.Kleiblova, P.Zemankova, P.Stastna, B.Janatova, M.Soukupova, J.Achatz, M.I.Ambrosone, C.Apostolou, P.Arun, B.K.Auer, P.Barnard, M.Bertelsen, B.Blok, M.J.Boddicker, N.Brunet, J.Burnside, E.S.Calvello, M.Campbell, I.Chan, S.H.Chen, F.Chiang, J.B.Coppa, A.Cortesi, L.Crujeiras-González, A.De Leeneer, K.De Putter, R.DePersia, A.Devereux, L.Domchek, S.Efremidis, A.Engel, C.Ernst, C.Evans, D.G.R.Feliubadaló, L.Fostira, F.Fuentes-Ríos, O.Gómez-García, E.B.González, S.Haiman, C.Hansen, T.V.O.Hauke, J.Hodge, J.Hu, C.Huang, H.Ishak, N.D.B.Iwasaki, Y.Konstantopoulou, I.Kraft, P.Lacey, J.Lázaro, C.Li, N.Lim, W.K.Lindstrom, S.Lori, A.Martinez, E.Martins, A.Matsuda, K.Matullo, G.McInerny, S.Michailidou, K.Montagna, M.Monteiro, A.N.A.Mori, L.Nathanson, K.Neuhausen, S.L.Nevanlinna, H.Olson, J.E.Palmer, J.Pasini, B.Patel, A.Piane, M.Poppe, B.Radice, P.Renieri, A.Resta, N.Richardson, M.E.Rosseel, T.Ruddy, K.J.Santamariña Pena, MartaDos Santos, E.S.Teras, L.Toland, A.E.Trentham-Dietz, A.Vachon, C.M.Volk, A.E.Weber-Lassalle, N.Weitzel, J.N.Wiesmuller, L.Winham, S.Yadav, S.Yannoukakos, D.Yao, S.Zampiga, V.Zethoven, M.Zhang, Z.W.Zima, T.Spurdle, A.B.Vega Gliemmo, AnaRossing, M.Del Valle, J.De Nicolo, A.Hahnen, E.Claes, K.B.M.Ngeow, J.Momozawa, Y.James, P.A.Couch, F.J.Macurek, L.Kleibl, Z.HumansFemaleBreast NeoplasmsGenetic Predisposition to DiseaseCheckpoint Kinase 2Mutation, MissenseGerm-Line MutationGerm CellsFPGMXFPGMXPURPOSE: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ? 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). EXPERIMENTAL DESIGN: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. RESULTS: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results. CONCLUSIONS: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.This work was supported by the grant projects of the Czech Ministry of Health NV19-03-00279, DRO-VFN-64165; Charles University projects COOPERATIO and SVV260516; Ministry of Education, Youths and Sports of the Czech Republic grant EXCELES no. LX22NPO05102 funded by EU. L. Stolarova was partially supported by Czech Academy of Science (PPPLZ project L200522201) . The CARRIERS study was supported by NIH grants R01 CA192393, R35 CA253187 and a specialized program of research excellence (SPORE) in breast cancer (P50 CA116201) . Contract grant sponsor A. Vega: supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (PI22/00589, PI19/01424; INT20/00071) , the Autonomous Government of Galicia (Consolidation and structuring program: IN607B) , by the Fundacion Mutua Madrilena (call 2018) , and by the AECC (PRYES211091VEGA) . A.B. Spurdle was supported by an NHMRC Investigator Fellowship (APP177524) .The Biobank Japan, in Addition to Those Named in the Author List: Koichi Matsuda, Yoichiro Kamatani, Takayuki Morisaki, Akiko Nagai, Kaori Muto, Yoshi-nori Murakami, Yoichi Furukawa, Yuji Yamanashi, Yusuke Nakamura, (Institute of Medical Science, The University ofTokyo, Tokyo) ; Taisei Mushiroda, Yukihide Momozawa, Toshihiro Tanaka, Yozo Ohnishi, Michiaki Kubo (RIKEN Center for Integrative Medical Sciences, Yokohama) ; Shinichi Higashiue, Shuzo Kobayashi (Tokushukai Hospitals, Tokyo) ; Shiro Minami, Hiroki Yamaguhci (Nippon Medical School, Tokyo) ; Hajime Arai, Ken Yamaji, Yasushi Okazaki (Juntendo University, Tokyo) ; Satoshi Asai, Yasuo Takahashi (Nihon University, Tokyo) ; Tomoaki Fujioka, Wataru Obara (Iwate Medical University Iwate) ; Seijiro Mori, Shigeo Murayama (Tokyo Metropolitan Institute of Gerontology, Tokyo) ; Satoshi Nagayama, Yoshio Miki (The Cancer Institute Hospital of JFCR, Tokyo) ; Akihide Masumoto, Akira Yamada (Aso Iizuka Hospital, Fukuoka) ; Yasuko Nishizawa, Masahiko Higashiyama (Osaka International Center Institute, Osaka) Hiromu Kutsumi (Shiga University of Medical Science, Shiga) ; Yukihiro Koretsune (National Hospital Organization, Osaka National Hospital, Osaka) ; Takashi Yoshiyama (Fukujuji Hospital, Tokyo) . The CZECANCA consortium, in Addition to Those Named in the Author List: Marianna Borecka, Marta Cerna, Milena Hovhannisyan, Sandra Jelinkova, Petr Nehasil (Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine and General University Hospital in Prague, Prague) ; Lenka Foretova, Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno) ; Vera Krutilkova, Spiros Tavandzis (AGEL Laboratories, Novy Jicin) ; Leona Cerna, Stepan Chvojka, Monika Koudova, Alena Puchmajerova (GENNET, Prague) ; Ondrej Havranek, Jan Novotny, Kamila Vesela, Michal Vocka (Institute of Biology and Medical Genetics, First Faculty of Medicine and General University Hospital in Prague, Prague) ; Lucie Hruskova, Renata Michalovska, Denisa Schwetzova, Zdenka Vlckova (GHC Genetics, Prague) ; Monika Cerna, Marketa Hejnalova, Nikol Jedlickova, Ivan Subrt, Tomas Zavoral (Institute of Medical Genetics, University Hospital Pilsen, Pilsen) ; Marcela Kosarova, Gabriela Vacinova (PRONATAL, Prague) ; Maria Janikova, Romana Kratochvilova, Vaclava Curtisova, Radek Vrtel (Department of Medical Genetics, University Hospital Olomouc, Faculty of Medicine and Dentistry, Palacky University, Olomouc) ; Ondrej Scheinost, Petra Duskova (Hospital Ceske Budejovice, Ceske Budejovice) ; Viktor Stranecky (Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine and General University Hospital in Prague, Prague) .The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked advertisement in accordance with 18 USC section 1734.2023info:eu-repo/semantics/articlehttps://portalcientifico.sergas.gal//documentos/64f6355666ccc641d10d6b7ehttp://hdl.handle.net/20.500.11940/21475reponame:RUNA. Repositorio da Consellería de Sanidade e Sergasinstname:Servizo Galego de Saúde (SERGAS)Ingléshttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:runa.sergas.gal:20.500.11940/214752026-06-12T08:40:47Z |
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