Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families-Reference-Cited by-同舟云学术

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families

Published:2020-03-01 Issue:7 Volume:38 Page:674-685
ISSN:0732-183X
Container-title:Journal of Clinical Oncology
language:en
Short-container-title:JCO

Author:

Yang Xin¹,Leslie Goska¹,Doroszuk Alicja²,Schneider Sandra²,Allen Jamie¹,Decker Brennan¹³⁴,Dunning Alison M.⁵,Redman James²,Scarth James²,Plaskocinska Inga²,Luccarini Craig⁵,Shah Mitul⁵,Pooley Karen¹,Dorling Leila¹,Lee Andrew¹,Adank Muriel A.⁶,Adlard Julian⁷,Aittomäki Kristiina⁸,Andrulis Irene L.⁹,Ang Peter¹⁰,Barwell Julian¹¹,Bernstein Jonine L.¹²,Bobolis Kristie¹³,Borg Åke¹⁴,Blomqvist Carl¹⁵,Claes Kathleen B.M.¹⁶,Concannon Patrick¹⁷,Cuggia Adeline¹⁸¹⁹,Culver Julie O.²⁰,Damiola Francesca²¹,de Pauw Antoine²²,Diez Orland²³,Dolinsky Jill S.²⁴,Domchek Susan M.²⁵²⁶,Engel Christoph²⁷,Evans D. Gareth²⁸,Fostira Florentia²⁹,Garber Judy²⁶³⁰,Golmard Lisa²²,Goode Ellen L.³¹,Gruber Stephen B.³²,Hahnen Eric³³³⁴,Hake Christopher¹³,Heikkinen Tuomas³⁵,Hurley Judith E.³⁶,Janavicius Ramunas³⁷³⁸,Kleibl Zdenek³⁹,Kleiblova Petra³⁹⁴⁰,Konstantopoulou Irene²⁹,Kvist Anders¹⁴,Laduca Holly²⁴,Lee Ann S.G.¹¹⁴¹⁴²,Lesueur Fabienne⁴³,Maher Eamonn R.²,Mannermaa Arto⁴⁴,Manoukian Siranoush⁴⁵,McFarland Rachel²⁴⁴⁶,McKinnon Wendy⁴⁷,Meindl Alfons⁴⁸,Metcalfe Kelly⁴⁹,Mohd Taib Nur Aishah⁵⁰,Moilanen Jukka⁵¹,Nathanson Katherine L.²⁵,Neuhausen Susan⁵²,Ng Pei Sze⁵⁰⁵³,Nguyen-Dumont Tu⁵⁴⁵⁵,Nielsen Sarah M.⁵⁶,Obermair Florian⁵⁷,Offit Kenneth²⁶⁵⁸,Olopade Olufunmilayo I.⁵⁶,Ottini Laura⁵⁹,Penkert Judith⁶⁰,Pylkäs Katri⁶¹,Radice Paolo⁶²,Ramus Susan J.⁶³⁶⁴,Rudaitis Vilius³⁷,Side Lucy⁶⁵,Silva-Smith Rachel⁶⁶,Silvestri Valentina⁵⁹,Skytte Anne-Bine⁶⁷,Slavin Thomas¹³⁶⁸,Soukupova Jana³⁹,Tondini Carlo⁶⁹,Trainer Alison H.⁷⁰⁷¹,Unzeitig Gary¹³,Usha Lydia¹³,van Overeem Hansen Thomas⁷²⁷³,Whitworth James²,Wood Marie⁴⁷,Yip Cheng Har⁵³,Yoon Sook-Yee⁵³,Yussuf Amal²⁴,Zogopoulos George¹⁸¹⁹,Goldgar David⁷⁴,Hopper John L.⁷⁵,Chenevix-Trench Georgia⁷⁶,Pharoah Paul¹,George Sophia H.L.⁷⁷,Balmaña Judith²³²⁶,Houdayer Claude²²⁷⁸,James Paul⁷⁰⁷¹,El-Haffaf Zaki⁷⁹,Ehrencrona Hans⁸⁰⁸¹,Janatova Marketa³⁹,Peterlongo Paolo⁸²,Nevanlinna Heli³⁵,Schmutzler Rita³³³⁴,Teo Soo-Hwang⁵⁰⁵³,Robson Mark²⁶⁸³,Pal Tuya⁸⁴,Couch Fergus²⁶⁸⁵,Weitzel Jeffrey N.¹³⁶⁸,Elliott Aaron²⁴,Southey Melissa⁵⁴⁵⁵,Winqvist Robert⁶¹,Easton Douglas F.¹,Foulkes William D.¹⁸⁸⁶,Antoniou Antonis C.¹,Tischkowitz Marc²

Affiliation:

1. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom

2. Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom

3. Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

4. Department of Pathology, Brigham and Women’s Hospital, Boston, MA

5. Centre for Cancer Genetic Epidemiology, Department of Oncology,University of Cambridge, Cambridge, United Kingdom

6. Family Cancer Clinic, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands

7. Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom

8. Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland

9. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada

10. Laboratory of Molecular Oncology, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore

11. Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom

12. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY

13. Clinical Cancer Genomics Community Research Network, City of Hope, Duarte, CA

14. Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden

15. Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland

16. Centre for Medical Genetics, Ghent University, Ghent, Belgium

17. University of Florida Genetics Institute, University of Florida, Gainesville, FL

18. The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada

19. The Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada

20. Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA

21. Biopathologie, Centre Léon Bérard, Lyon, France

22. Service de Génétique, Institut Curie, Paris, France

23. Oncogenetics Group, Clinical and Molecular Genetics Area, Vall d’Hebron Institute of Oncology (VHIO), University Hospital, Vall d’Hebron, Barcelona, Spain

24. Ambry Genetics, Aliso Viejo, CA

25. Department ofMedicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

26. Prospective Registry of Multiplex Testing (PROMPT), United States and Europe

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

28. Division of Evolution and Genomic Sciences, University of Manchester; Manchester Centre for Genomic Medicine, St Mary’s Hospital–Manchester University Hospitals NHS Foundation Trust; and Manchester Academic Health Science Centre, Manchester, United Kingdom

29. Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research “Demokritos,” Athens, Greece

30. Dana-Farber Cancer Institute, Boston, MA

31. Department of Health Sciences Research, Mayo Clinic, Rochester, MN

32. City of Hope National Medical Center, Duarte, CA

33. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany

34. Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany

35. Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland

36. Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL

37. Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania

38. State Research Institute Innovative Medicine Center, Vilnius, Lithuania

39. Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic

40. Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic

41. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

42. SingHealth Duke-NUS Oncology Academic Clinical Programme (ONCO ACP), Duke-NUS Medical School, Singapore

43. INSERM U900, Institut Curie, PSL University, Mines ParisTech, Paris, France

44. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland

45. Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

46. Department of Epidemiology, University of California, Irvine, Irvine, CA

47. Familial Cancer Program, The University of Vermont Cancer Center, Burlington, VT

48. Department of Gynecology and Obstetrics, Ludwig-Maximilians University of Munich, Munich, Germany

49. Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada

50. University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia

51. Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu, Finland

52. Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA

53. Cancer Research Malaysia, Subang Jaya Selangor, Malaysia

54. Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia

55. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia

56. Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL

57. Institute of Medical Genetics, Kepler University Hospital Linz and Laboratory for Molecular Biology and Tumor Cytogenetics, Ordensklinikum Linz, Linz, Austria

58. Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

59. Department of Molecular Medicine, University La Sapienza, Rome, Italy

60. Department of Human Genetics, Hannover Medical School, Hannover, Germany

61. Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, and Northern Finland Laboratory Centre, Oulu, Finland

62. Unit of Molecular Basis of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

63. School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia

64. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

65. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom

66. Department of Genetics, University of MiamiMiller School of Medicine, Miami, FL

67. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark

68. Department of Medical Oncology, Division of Clinical Cancer Genomics, City of Hope, Duarte, CA

69. Unit of Medical Oncology, Department of Oncology and Hematology,Papa Giovanni XXIII Hospital, Bergamo, Italy

70. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

71. Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia

72. Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

73. Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

74. Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT

75. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia

76. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

77. Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL

78. Genetics Department, F76000 and Normandy University, UNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Rouen University Hospital, Rouen, France

79. Department of Genetics, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada

80. Department of Clinical Genetics and Pathology, Department of Laboratory Medicine, Office for Medical Services, Lund, Sweden

81. Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden

82. Genome Diagnostics Program, IFOM–The FIRC Institute for Molecular Oncology, Milan, Italy

83. Breast Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY

84. Vanderbilt-Ingram Cancer Center, Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN

85. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

86. Departments of Human Genetics, Oncology, and Medicine, McGill University, Montreal, Quebec, Canada

Abstract

PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10−76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10−3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10−3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10−2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( P for trend = 2.0 × 10−3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

Link

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.19.01907

Reference43 articles.

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