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

Yang X 1 , Leslie G 1 , Doroszuk A 2 , Schneider S 2 , Allen J 1 , Decker B 1 Show all authors , Dunning AM 3 , Redman J 2 , Scarth J 2 , Plaskocinska I 2 , Luccarini C 3 , Shah M 3 , Pooley K 1 , Dorling L 1 , Lee A 1 , Adank MA 4 , Adlard J 5 , Aittomäki K 6 , Andrulis IL 7 , Ang P 8 , Barwell J 9 , Bernstein JL 10 , Bobolis K 11 , Borg Å 12 , Blomqvist C 13 , Claes KBM 14 , Concannon P 15 , Cuggia A 16 , Culver JO 17 , Damiola F 18 , de Pauw A 19 , Diez O 20 , Dolinsky JS 21 , Domchek SM 22 , Engel C 23 , Evans DG 24 , Fostira F 25 , Garber J 26 , Golmard L 19 , Goode EL 27 , Gruber SB 28 , Hahnen E 29 , Hake C 11 , Heikkinen T 30 , Hurley JE 31 , Janavicius R 32 , Kleibl Z 33 , Kleiblova P 33 , Konstantopoulou I 25 , Kvist A 12 , Laduca H 21 , Lee ASG 9 , Lesueur F 34 , Maher ER 2 , Mannermaa A 35 , Manoukian S 36 , McFarland R 21 , McKinnon W 37 , Meindl A 38 , Metcalfe K 39 , Mohd Taib NA 40 , Moilanen J 41 , Nathanson KL 22 , Neuhausen S 42 , Ng PS 40 , Nguyen-Dumont T 43 , Nielsen SM 44 , Obermair F 45 , Offit K 26 , Olopade OI 44 , Ottini L 46 , Penkert J 47 , Pylkäs K 48 , Radice P 49 , Ramus SJ 50 , Rudaitis V 32 , Side L 51 , Silva-Smith R 52 , Silvestri V 46 , Skytte AB 53 , Slavin T 11 , Soukupova J 33 , Tondini C 54 , Trainer AH 55 , Unzeitig G 11 , Usha L 11 , van Overeem Hansen T 56 , Whitworth J 2 , Wood M 37 , Yip CH 57 , Yoon SY 57 , Yussuf A 21 , Zogopoulos G 16 , Goldgar D 58 , Hopper JL 59 , Chenevix-Trench G 60 , Pharoah P 1 , George SHL 61 , Balmaña J 20 , Houdayer C 19 , James P 55 , El-Haffaf Z 62 , Ehrencrona H 63 , Janatova M 33 , Peterlongo P 64 , Nevanlinna H 30 , Schmutzler R 29 , Teo SH 40 , Robson M 26 , Pal T 65 , Couch F 26 , Weitzel JN 11 , Elliott A 21 , Southey M 43 , Winqvist R 48 , Easton DF 1 , Foulkes WD 16 , Antoniou AC 1 , Tischkowitz M 2

Affiliations 

  • 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 Centre for Cancer Genetic Epidemiology, Department of Oncology,University of Cambridge, Cambridge, United Kingdom
  • 4 Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
  • 5 Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom
  • 6 Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 7 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
  • 8 Laboratory of Molecular Oncology, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
  • 9 Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
  • 10 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
  • 11 Clinical Cancer Genomics Community Research Network, City of Hope, Duarte, CA
  • 12 Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
  • 13 Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 14 Centre for Medical Genetics, Ghent University, Ghent, Belgium
  • 15 University of Florida Genetics Institute, University of Florida, Gainesville, FL
  • 16 The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada
  • 17 Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA
  • 18 Biopathologie, Centre Léon Bérard, Lyon, France
  • 19 Service de Génétique, Institut Curie, Paris, France
  • 20 Oncogenetics Group, Clinical and Molecular Genetics Area, Vall d'Hebron Institute of Oncology (VHIO), University Hospital, Vall d'Hebron, Barcelona, Spain
  • 21 Ambry Genetics, Aliso Viejo, CA
  • 22 Department ofMedicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
  • 23 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  • 24 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
  • 25 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos," Athens, Greece
  • 26 Prospective Registry of Multiplex Testing (PROMPT), United States and Europe
  • 27 Department of Health Sciences Research, Mayo Clinic, Rochester, MN
  • 28 City of Hope National Medical Center, Duarte, CA
  • 29 Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
  • 30 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 31 Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL
  • 32 Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania
  • 33 Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
  • 34 INSERM U900, Institut Curie, PSL University, Mines ParisTech, Paris, France
  • 35 Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland
  • 36 Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  • 37 Familial Cancer Program, The University of Vermont Cancer Center, Burlington, VT
  • 38 Department of Gynecology and Obstetrics, Ludwig-Maximilians University of Munich, Munich, Germany
  • 39 Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada
  • 40 University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
  • 41 Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu, Finland
  • 42 Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA
  • 43 Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia
  • 44 Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL
  • 45 Institute of Medical Genetics, Kepler University Hospital Linz and Laboratory for Molecular Biology and Tumor Cytogenetics, Ordensklinikum Linz, Linz, Austria
  • 46 Department of Molecular Medicine, University La Sapienza, Rome, Italy
  • 47 Department of Human Genetics, Hannover Medical School, Hannover, Germany
  • 48 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
  • 49 Unit of Molecular Basis of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  • 50 School of Women's and Children's Health, Faculty of Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia
  • 51 Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom
  • 52 Department of Genetics, University of MiamiMiller School of Medicine, Miami, FL
  • 53 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
  • 54 Unit of Medical Oncology, Department of Oncology and Hematology,Papa Giovanni XXIII Hospital, Bergamo, Italy
  • 55 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
  • 56 Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 57 Cancer Research Malaysia, Subang Jaya Selangor, Malaysia
  • 58 Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT
  • 59 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
  • 60 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 61 Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL
  • 62 Department of Genetics, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
  • 63 Department of Clinical Genetics and Pathology, Department of Laboratory Medicine, Office for Medical Services, Lund, Sweden
  • 64 Genome Diagnostics Program, IFOM-The FIRC Institute for Molecular Oncology, Milan, Italy
  • 65 Vanderbilt-Ingram Cancer Center, Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
J Clin Oncol, 2020 03 01;38(7):674-685.
PMID: 31841383 DOI: 10.1200/JCO.19.01907

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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