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Cancer risks associated with germline PALB2 pathogenic variants: An international study of 524 families

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DOI

  • Xin Yang, Cambridge University
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  • Goska Leslie, Cambridge University
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  • Alicja Doroszuk, Cambridge University
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  • Sandra Schneider, Cambridge University
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  • Jamie Allen, Cambridge University
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  • Brennan Decker, Cambridge University, National Human Genome Research Institute, Brigham and Women's Hospital, Boston
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  • Alison M. Dunning, Cambridge University
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  • James Redman, Cambridge University
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  • James Scarth, Cambridge University
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  • Inga Plaskocinska, Cambridge University
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  • Craig Luccarini, Cambridge University
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  • Mitul Shah, Cambridge University
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  • Karen Pooley, Cambridge University
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  • Leila Dorling, Cambridge University
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  • Andrew Leei, Cambridge University
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  • Muriel A. Adank, Antoni van Leeuwenhoek Hospital
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  • Julian Adlard, Chapel Allerton Hospital
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  • Kristiina Aittomäki, Helsinki University Central Hospital
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  • Irene L. Andrulis, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
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  • Peter Ang, National Cancer Centre
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  • Julian Barwell, University Hospitals of Leicester NHS Trust
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  • Jonine L. Bernstein, Memorial Sloan-Kettering Cancer Center
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  • Kristie Bobolis, Clinical Cancer Genomics Community Research Network
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  • Åke Borg, Lund University
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  • Carl Blomqvist, Helsinki University Central Hospital
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  • Kathleen B.M. Claes, Ghent University Hospital, Ghent
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  • Patrick Concannon, University of Florida, Gainesville, Florida
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  • Adeline Cuggia, Research Institute of the McGill University Health Centre, McGill University
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  • Julie O. Culver, University of Southern California/Norris Comprehensive Cancer Center
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  • Francesca Damiola, Centre Leon Berard
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  • Antoine De Pauw, Institut Curie
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  • Orland Diez, Vall d'Hebron Institute of Oncology
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  • Jill S. Dolinsky, Ambry Genetics
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  • Susan M. Domchek, University of Pennsylvania, United States and Europe
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  • Christoph Engel, Leipzig University
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  • D. Gareth Evans, University of Manchester
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  • Florentia Fostira, Demokritos National Centre for Scientific Research
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  • Judy Garber, United States and Europe, Dana-Farber Cancer Institute
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  • Lisa Golmard, Institut Curie
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  • Ellen L. Goode, Mayo Clinic Rochester, MN
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  • Stephen B. Gruber, Beckman Research Institute of the City of Hope
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  • Eric Hahnen, Universitat zu Koln, University of Cologne
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  • Christopher Hake, Clinical Cancer Genomics Community Research Network
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  • Tuomas Heikkinen, Helsinki University Central Hospital
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  • Judith E. Hurley, University of Miami
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  • Ramunas Janavicius, Vilnius University, State Research Institute Innovative Medicine Center
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  • Zdenek Kleibl, Charles University
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  • Petra Kleiblova, Charles University
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  • Irene Konstantopoulou, Demokritos National Centre for Scientific Research
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  • Anders Kvist, Lund University
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  • Holly Laduca, Ambry Genetics
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  • Ann S.G. Lee, University Hospitals of Leicester NHS Trust, Yong Loo Lin School of Medicine, Duke-NUS Graduate Medical School
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  • Fabienne Lesueur, Institut National de la Santé et de la Recherche Médicale
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  • Eamonn R. Maher, Cambridge University
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  • Arto Mannermaa, University of Eastern Finland
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  • Siranoush Manoukian, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
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  • Rachel McFarland, Ambry Genetics, UC Irvine
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  • Wendy McKinnon, University of Vermont
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  • Alfons Meindl, Ludwig-Maximilians-University München
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  • Kelly Metcalfe, University Toronto
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  • Nur Aishah Mohd Taib, University of Malaya
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  • Jukka Moilanen, Oulu University Hospital, Oulu
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  • Katherine L. Nathanson, University of Pennsylvania
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  • Susan Neuhausen, Beckman Research Institute of the City of Hope
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  • Pei Sze Ng, University of Malaya, Cancer Research Malaysia
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  • Tu Nguyen-Dumont, University of Melbourne, Monash University
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  • Sarah M. Nielsen, Center for Clinical Cancer Genetics, University of Chicago, Chicago, Illinois.
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  • Florian Obermair, Kepler University Hospital
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  • Kenneth Offit, United States and Europe, Memorial Sloan-Kettering Cancer Center
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  • Olufunmilayo I. Olopade, University of Chicago, Chicago, Illinois.
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  • Laura Ottini, University of Rome La Sapienza
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  • Judith Penkert, Hannover Medical School
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  • Katri Pylkäs, University of Oulu
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  • Paolo Radice, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
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  • Susan J. Ramus, University of New South Wales, Garvan Institute of Medical Research
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  • Vilius Rudaitis, Vilnius University
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  • Lucy Side, Princess Anne Hospital
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  • Rachel Silva-Smith, University of Miami Leonard M. Miller School of Medicine
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  • Valentina Silvestri, University of Rome La Sapienza
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  • Anne Bine Skytte
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  • Thomas Slavin, Clinical Cancer Genomics Community Research Network, Beckman Research Institute of the City of Hope
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  • Jana Soukupova, Charles University
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  • Carlo Tondini, Papa Giovanni XXIII Hospital
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  • Alison H. Trainer, University of Melbourne, Peter Maccallum Cancer Centre
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  • Gary Unzeitig, Clinical Cancer Genomics Community Research Network
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  • Lydia Usha, Clinical Cancer Genomics Community Research Network
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  • Thomas Van Overeem Hansen, Rigshospitalet
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  • James Whitworth, Cambridge University
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  • Marie Wood, University of Vermont
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  • Cheng Har Yip, Cancer Research Malaysia
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  • Sook Yee Yoon, Cancer Research Malaysia
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  • Amal Yussuf, Ambry Genetics
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  • George Zogopoulos, Research Institute of the McGill University Health Centre, McGill University
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  • David Goldgar, University of Utah
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  • John L. Hopper, Melbourne School of Population and Global Health
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  • Georgia Chenevix-Trench, Queensland Institute of Medical Research
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  • Paul Pharoah, Cambridge University
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  • Sophia H.L. George, University of Miami
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  • Judith Balmaña, Vall d'Hebron Institute of Oncology, United States and Europe
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  • Claude Houdayer, Institut Curie, Institut National de la Santé et de la Recherche Médicale
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  • Paul James, University of Melbourne, Peter Maccallum Cancer Centre
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  • Zaki El-Haffaf, Université de Montréal
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  • Hans Ehrencrona, Department of Clinical Genetics and Pathology, Lund University, Office for Medical Services, Lunds Universitet
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  • Marketa Janatova, Charles University
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  • Paolo Peterlongo, IFOM, Fondazione Istituto FIRC di Oncologia Molecolare.
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  • Heli Nevanlinna, Helsinki University Central Hospital
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  • Rita Schmutzler, Universitat zu Koln, University of Cologne
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  • Soo Hwang Teo, University of Malaya, Cancer Research Malaysia
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  • Mark Robson, United States and Europe, Memorial Sloan-Kettering Cancer Center
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  • Tuya Pal, Vanderbilt University School of Medicine
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  • Fergus Couch, United States and Europe, Mayo Clinic Rochester, MN
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  • Jeffrey N. Weitzel, Clinical Cancer Genomics Community Research Network, Beckman Research Institute of the City of Hope
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  • Aaron Elliott, Ambry Genetics
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  • Melissa Southey, University of Melbourne, Monash University
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  • Robert Winqvist, University of Oulu
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  • Douglas F. Easton, Cambridge University
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  • William D. Foulkes, Research Institute of the McGill University Health Centre, McGill University
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  • Antonis C. Antoniou, Cambridge University
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  • Marc Tischkowitz, Cambridge University

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 3 1022). 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.

Original languageEnglish
JournalJournal of Clinical Oncology
Volume38
Issue7
Pages (from-to)674-685
Number of pages12
ISSN0732-183X
DOIs
Publication statusPublished - 2020

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