ENIGMA<i>CHEK2</i>gether Project: A Comprehensive Study Identifies Functionally Impaired<i>CHEK2</i>Germline Missense Variants Associated with Increased Breast Cancer Risk-Reference-Cited by-同舟云学术

ENIGMACHEK2gether Project: A Comprehensive Study Identifies Functionally ImpairedCHEK2Germline Missense Variants Associated with Increased Breast Cancer Risk

Published:2023-07-13 Issue:16 Volume:29 Page:3037-3050
ISSN:1078-0432
Container-title:Clinical Cancer Research
language:en
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Author:

Stolarova Lenka¹^ORCID,Kleiblova Petra²³^ORCID,Zemankova Petra²⁴^ORCID,Stastna Barbora²^ORCID,Janatova Marketa²^ORCID,Soukupova Jana²^ORCID,Achatz Maria Isabel⁵^ORCID,Ambrosone Christine⁶⁷^ORCID,Apostolou Paraskevi⁸^ORCID,Arun Banu K.⁹^ORCID,Auer Paul¹⁰¹¹^ORCID,Barnard Mollie¹²^ORCID,Bertelsen Birgitte¹³^ORCID,Matsuda Koichi,Kamatani Yoichiro,Morisaki Takayuki,Nagai Akiko,Muto Kaori,Murakami Yoshinori,Furukawa Yoichi,Yamanashi Yuji,Nakamura Yusuke,Mushiroda Taisei,Momozawa Yukihide,Tanaka Toshihiro,Ohnishi Yozo,Kubo Michiaki,Higashiue Shinichi,Kobayashi Shuzo,Minami Shiro,Yamaguhci Hiroki,Arai Hajime,Yamaji Ken,Okazaki Yasushi,Asai Satoshi,Takahashi Yasuo,Fujioka Tomoaki,Obara Wataru,Mori Seijiro,Murayama Shigeo,Nagayama Satoshi,Miki Yoshio,Masumoto Akihide,Yamada Akira,Nishizawa Yasuko,Higashiyama Masahiko,Kutsumi Hiromu,Koretsune Yukihiro,Yoshiyama Takashi,Blok Marinus J.¹⁴^ORCID,Boddicker Nicholas¹⁵¹⁶^ORCID,Brunet Joan¹⁷¹⁸^ORCID,Burnside Elizabeth S.¹⁹²⁰^ORCID,Calvello Mariarosaria²¹^ORCID,Campbell Ian²²²³^ORCID,Chan Sock Hoai²⁴²⁵^ORCID,Chen Fei²⁶²⁷^ORCID,Chiang Jian Bang²⁴^ORCID,Coppa Anna²⁸^ORCID,Cortesi Laura²⁹^ORCID,Crujeiras-González Ana³⁰³¹^ORCID,Borecka Marianna,Cerna Marta,Hovhannisyan Milena,Jelinkova Sandra,Nehasil Petr,Foretova Lenka,Machackova Eva,Krutilkova Vera,Tavandzis Spiros,Cerna Leona,Chvojka Stepan,Koudova Monika,Puchmajerova Alena,Havranek Ondrej,Novotny Jan,Vesela Kamila,Vocka Michal,Hruskova Lucie,Michalovska Renata,Schwetzova Denisa,Vlckova Zdenka,Cerna Monika,Hejnalova Marketa,Jedlickova Nikol,Subrt Ivan,Zavoral Tomas,Kosarova Marcela,Vacinova Gabriela,Janikova Maria,Kratochvilova Romana,Curtisova Vaclava,Vrtel Radek,Scheinost Ondrej,Duskova Petra,Stranecky Viktor,De Leeneer Kim³²^ORCID,De Putter Robin³²^ORCID,DePersia Allison³³^ORCID,Devereux Lisa²³³⁴^ORCID,Domchek Susan¹⁶³⁵^ORCID,Efremidis Anna³⁶^ORCID,Engel Christoph³⁷^ORCID,Ernst Corinna³⁸^ORCID,Evans D. Gareth R.³⁹^ORCID,Feliubadaló Lidia¹⁷¹⁸^ORCID,Fostira Florentia⁴⁰^ORCID,Fuentes-Ríos Olivia³⁰³¹^ORCID,Gómez-García Encarna B.¹⁴^ORCID,González Sara¹⁷¹⁸^ORCID,Haiman Christopher²⁶²⁷^ORCID,Hansen Thomas van Overeem⁴¹⁴²^ORCID,Hauke Jan³⁸^ORCID,Hodge James⁴³⁴⁴^ORCID,Hu Chunling¹⁶⁴⁵^ORCID,Huang Hongyan⁴⁶⁴⁷^ORCID,Ishak Nur Diana Binte²⁴^ORCID,Iwasaki Yusuke⁴⁸^ORCID,Konstantopoulou Irene⁴⁰^ORCID,Kraft Peter⁴⁶⁴⁷^ORCID,Lacey James⁴⁹⁵⁰^ORCID,Lázaro Conxi¹⁷¹⁸^ORCID,Li Na²²^ORCID,Lim Weng Khong⁵¹^ORCID,Lindstrom Sara¹¹⁵²^ORCID,Lori Adriana⁴³⁵³^ORCID,Martinez Elana⁵¹⁵⁴^ORCID,Martins Alexandra⁵⁵^ORCID,Matsuda Koichi⁵⁶^ORCID,Matullo Giuseppe⁵⁷^ORCID,McInerny Simone⁵⁸^ORCID,Michailidou Kyriaki⁵⁹^ORCID,Montagna Marco⁶⁰^ORCID,Monteiro Alvaro N.A.⁶¹^ORCID,Mori Luigi⁶²⁶³^ORCID,Nathanson Katherine¹⁶³⁵^ORCID,Neuhausen Susan L.⁶⁴^ORCID,Nevanlinna Heli⁶⁵^ORCID,Olson Janet E.¹⁵⁶⁶^ORCID,Palmer Julie¹²^ORCID,Pasini Barbara⁵⁷^ORCID,Patel Alpa⁶⁷⁶⁸^ORCID,Piane Maria⁶⁹^ORCID,Poppe Bruce³²^ORCID,Radice Paolo⁷⁰^ORCID,Renieri Alessandra⁷¹^ORCID,Resta Nicoletta⁷²^ORCID,Richardson Marcy E.⁷³^ORCID,Rosseel Toon³²^ORCID,Ruddy Kathryn J.⁶⁶⁷⁴^ORCID,Santamariña Marta³⁰³¹⁷⁵^ORCID,Dos Santos Elizabeth Santana⁵^ORCID,Teras Lauren⁶⁷⁶⁸^ORCID,Toland Amanda E.⁷⁶^ORCID,Trentham-Dietz Amy²⁰⁷⁷^ORCID,Vachon Celine M.⁷⁸⁷⁹^ORCID,Volk Alexander E.⁸⁰^ORCID,Weber-Lassalle Nana³⁸^ORCID,Weitzel Jeffrey N.¹⁶⁸¹^ORCID,Wiesmuller Lisa⁸²^ORCID,Winham Stacey⁷⁹⁸³^ORCID,Yadav Siddhartha¹⁶⁸⁴^ORCID,Yannoukakos Drakoulis⁴⁰^ORCID,Yao Song⁷⁸⁵^ORCID,Zampiga Valentina⁸⁶^ORCID,Zethoven Magnus²²^ORCID,Zhang Ze Wen²⁴^ORCID,Zima Tomas²^ORCID,Spurdle Amanda B.⁸⁷^ORCID,Vega Ana³⁰³¹⁷⁵^ORCID,Rossing Maria¹³^ORCID,Del Valle Jesús¹⁷¹⁸^ORCID,De Nicolo Arcangela⁸⁸^ORCID,Hahnen Eric³⁸^ORCID,Claes Kathleen B.M.³²^ORCID,Ngeow Joanne²⁴²⁵^ORCID,Momozawa Yukihide⁴⁸^ORCID,James Paul A.²³⁵⁵^ORCID,Couch Fergus J.¹⁶⁴³^ORCID,Macurek Libor¹^ORCID,Kleibl Zdenek²⁴^ORCID, ,

Affiliation:

1. 1Laboratory of Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.

2. 2Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

3. 3Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

4. 4Department of Pathophysiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.

5. 5A.C. Camargo Cancer Center and Oncology Center, Hospital Sirio-Libanes, Sao Paulo, Brazil.

6. 6Department of Cancer Prevention & Control, Roswell Park Cancer Center, Buffalo, New York.

7. 7WCHS Inc., Baltimore, Maryland.

8. 8Human Molecular Genetics Laboratory, INRaSTES, National Center for Scientific Research "Demokritos," Athens, Greece.

9. 9Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

10. 10Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.

11. 11WHI, USA.

12. 12Slone Epidemiology Center, Boston University, Boston, Massachusetts.

13. 13Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark.

14. 15Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.

15. 16Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.

16. 17CARRIERS, USA.

17. 18Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.

18. 19Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL-IGTP-IDIBGI, L'Hospitalet, Barcelona, Spain.

19. 20School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.

20. 21WWHS, Charlotte, North Carolina.

21. 22Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, Milan, Italy.

22. 23Cancer Genomics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia.

23. 24Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.

24. 25Cancer Genetics Service, National Cancer Centre, Singapore, Singapore.

25. 26Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.

26. 27Keck School of Medicine, University of Southern California, Los Angeles, California.

27. 28MEC, USA.

28. 29Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

29. 30Department of Oncology and Haematology, Modena University Hospital, Modena, Italy.

30. 31Fundacion Publica Galega de Medicina Xenomica, Santiago de Compostela, Spain.

31. 32Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain.

32. 33Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

33. 34Center for Medical Genetics, NorthShore University Health System, Evanston, Illinois.

34. 35Lifepool, Peter MacCallum Cancer Centre, Melbourne, Australia.

35. 36Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

36. 37Clinical Cancer Genetics and Family Consultants, CLINICAGENE, Athens Medical Center, Athens, Greece.

37. 38Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.

38. 39Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

39. 40Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, United Kingdom.

40. 41Molecular Diagnostics Laboratory, INRaSTES, National Center for Scientific Research "Demokritos," Athens, Greece.

41. 42Department of Clinical Genetics, Copenhagen University Hospital, Copenhagen, Denmark.

42. 43Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark.

43. 44Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.

44. 45CPS3, Kennesaw, Georgia.

45. 46Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

46. 47T.H. Chan School of Public Health, Harvard University, Cambridge, Massachusetts.

47. 48NHS, Reston, Virginia.

48. 49Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

49. 50Beckman Research Institute, City of Hope Cancer Center, Duarte, California.

50. 51CTS, USA.

51. 52Duke-NUS Medical School, Singapore, Singapore.

52. 53Department of Epidemiology, University of Washington, Seattle, Washington.

53. 54American Cancer Society, Atlanta, Georgia.

54. 55Department of Family Medicine and Public Health, University of California San Diego, San Diego, California.

55. 56Inserm UMR1245, UNIROUEN, Normandy Centre for Genomic and Personalized Medicine, Normandie University, Rouen, France.

56. 57Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

57. 58Department of Medical Sciences, University of Turin, Turin, Italy.

58. 59Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, and Royal Melbourne Hospital, Melbourne, Australia.

59. 60Biostatistics Unit, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

60. 61Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, Padua, Italy.

61. 62Cancer Epidemiology Program, Division of Population Sciences, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.

62. 63Endocrine and Metabolic Disease Unit, ASST Spedali Civili of Brescia, Brescia, Italia.

63. 64Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

64. 65Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California.

65. 66Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

66. 67MCBCS, USA.

67. 68Department of Population Science, American Cancer Society, Atlanta, Georgia.

68. 69CPS-II, USA.

69. 70Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy.

70. 71Department of Experimental Oncology, Molecular Bases of Genetic Risk and Genetic Testing Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

71. 72Medical genetics, University of Siena, Siena, Italy.

72. 73Department of Precision and Regenerative Medicine and Ionian Area, Medical Genetics Unit, University of Bari, Bari, Italy.

73. 74Ambry Genetics, Aliso Viejo, California.

74. 75Department of Oncology, Mayo Clinic, Rochester, Minnesota.

75. 76Centro de Investigación en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.

76. 77Department of Cancer Biology & Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

77. 78University of Wisconsin, Madison, Wisconsin.

78. 79Mayo Clinic, Rochester, Minnesota.

79. 80MMHS, USA.

80. 81Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

81. 82Natera Inc., Duarte, California.

82. 83Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany.

83. 84Department Quantitative Sciences, Mayo Clinic, Rochester, Minnesota.

84. 85Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.

85. 86Roswell Park Comprehensive Cancer Center, Buffalo, New York.

86. 87Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori," Meldola, Italy.

87. 88Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

88. 89Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Abstract

AbstractPurpose: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.

Funder

Ministerstvo Zdravotnictví Ceské Republiky

Ministerstvo Školství, Mládeže a Tělovýchovy

Charles University

Akademie Věd České Republiky

National Cancer Institute

Instituto de Salud Carlos III

Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Fund

Autonomous Government of Galicia

Fundación Mutua Madrileña

Fundación Científica Asociación Española Contra el Cáncer

National Health and Medical Research Council