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J Clin Oncol. 2019 Dec 16:JCO1901907. doi: 10.1200/JCO.19.01907. [Epub ahead of print]

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

Yang X1, Leslie G1, Doroszuk A2, Schneider S2, Allen J1, Decker B1,3,4, Dunning AM5, Redman J2, Scarth J2, Plaskocinska I2, Luccarini C5, Shah M5, Pooley K1, Dorling L1, Lee A1, Adank MA6, Adlard J7, Aittomäki K8, Andrulis IL9, Ang P10, Barwell J11, Bernstein JL12, Bobolis K13, Borg Å14, Blomqvist C15, Claes KBM16, Concannon P17, Cuggia A18,19, Culver JO20, Damiola F21, de Pauw A22, Diez O23, Dolinsky JS24, Domchek SM25,26, Engel C27, Evans DG28, Fostira F29, Garber J26,30, Golmard L22, Goode EL31, Gruber SB32, Hahnen E33,34, Hake C13, Heikkinen T35, Hurley JE36, Janavicius R37,38, Kleibl Z39, Kleiblova P39,40, Konstantopoulou I29, Kvist A14, Laduca H24, Lee ASG11,41,42, Lesueur F43, Maher ER2, Mannermaa A44, Manoukian S45, McFarland R24,46, McKinnon W47, Meindl A48, Metcalfe K49, Mohd Taib NA50, Moilanen J51, Nathanson KL25, Neuhausen S52, Ng PS50,53, Nguyen-Dumont T54,55, Nielsen SM56, Obermair F57, Offit K26,58, Olopade OI56, Ottini L59, Penkert J60, Pylkäs K61, Radice P62, Ramus SJ63,64, Rudaitis V37, Side L65, Silva-Smith R66, Silvestri V59, Skytte AB67, Slavin T13,68, Soukupova J39, Tondini C69, Trainer AH70,71, Unzeitig G13, Usha L13, van Overeem Hansen T72,73, Whitworth J2, Wood M47, Yip CH53, Yoon SY53, Yussuf A24, Zogopoulos G18,19, Goldgar D74, Hopper JL75, Chenevix-Trench G76, Pharoah P1, George SHL77, Balmaña J23,26, Houdayer C22,78, James P70,71, El-Haffaf Z79, Ehrencrona H80,81, Janatova M39, Peterlongo P82, Nevanlinna H35, Schmutzler R33,34, Teo SH50,53, Robson M26,83, Pal T84, Couch F26,85, Weitzel JN13,68, Elliott A24, Southey M54,55, Winqvist R61, Easton DF1, Foulkes WD18,86, Antoniou AC1, Tischkowitz M2.

Author information

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.

PMID:
31841383
DOI:
10.1200/JCO.19.01907

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