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

  • Xin Yang
  • , Goska Leslie
  • , Alicja Doroszuk
  • , Sandra Schneider
  • , Jamie Allen
  • , Brennan Decker
  • , Alison M. Dunning
  • , James Redman
  • , James Scarth
  • , Inga Plaskocinska
  • , Craig Luccarini
  • , Mitul Shah
  • , Karen Pooley
  • , Leila Dorling
  • , Andrew Leei
  • , Muriel A. Adank
  • , Julian Adlard
  • , Kristiina Aittomäki
  • , Irene L. Andrulis
  • , Peter Ang
    • Julian Barwell, Jonine L. Bernstein, Kristie Bobolis, Åke Borg, Carl Blomqvist, Kathleen B.M. Claes, Patrick Concannon, Adeline Cuggia, Julie O. Culver, Francesca Damiola, Antoine De Pauw, Orland Diez, Jill S. Dolinsky, Susan M. Domchek, Christoph Engel, D. Gareth Evans, Florentia Fostira, Judy Garber, Lisa Golmard, Ellen L. Goode, Stephen B. Gruber, Eric Hahnen, Christopher Hake, Tuomas Heikkinen, Judith E. Hurley, Ramunas Janavicius, Zdenek Kleibl, Petra Kleiblova, Irene Konstantopoulou, Anders Kvist, Holly Laduca, Ann S.G. Lee, Fabienne Lesueur, Eamonn R. Maher, Arto Mannermaa, Siranoush Manoukian, Rachel McFarland, Wendy McKinnon, Alfons Meindl, Kelly Metcalfe, Nur Aishah Mohd Taib, Jukka Moilanen, Katherine L. Nathanson, Susan Neuhausen, Pei Sze Ng, Tu Nguyen-Dumont, Sarah M. Nielsen, Florian Obermair, Kenneth Offit, Olufunmilayo I. Olopade, Laura Ottini, Judith Penkert, Katri Pylkäs, Paolo Radice, Susan J. Ramus, Vilius Rudaitis, Lucy Side, Rachel Silva-Smith, Valentina Silvestri, Anne Bine Skytte, Thomas Slavin, Jana Soukupova, Carlo Tondini, Alison H. Trainer, Gary Unzeitig, Lydia Usha, Thomas Van Overeem Hansen, James Whitworth, Marie Wood, Cheng Har Yip, Sook Yee Yoon, Amal Yussuf, George Zogopoulos, David Goldgar, John L. Hopper, Georgia Chenevix-Trench, Paul Pharoah, Sophia H.L. George, Judith Balmaña, Claude Houdayer, Paul James, Zaki El-Haffaf, Hans Ehrencrona, Marketa Janatova, Paolo Peterlongo, Heli Nevanlinna, Rita Schmutzler, Soo Hwang Teo, Mark Robson, Tuya Pal, Fergus Couch, Jeffrey N. Weitzel, Aaron Elliott, Melissa Southey, Robert Winqvist, Douglas F. Easton, William D. Foulkes, Antonis C. Antoniou, Marc Tischkowitz*
*Corresponding author for this work
  • University of Cambridge
  • National Human Genome Research Institute (NHGRI)
  • Brigham and Women's Hospital
  • Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital
  • Chapel Allerton Hospital
  • Helsinki University Hospital
  • Mount Sinai Hospital of University of Toronto
  • National Cancer Centre Singapore
  • University Hospitals of Leicester National Health Service (NHS) Trust
  • Department of Medicine
  • Clinical Cancer Genomics Community Research Network
  • Lund University
  • Ghent University Hospital
  • University of Central Florida
  • McGill University
  • University of Southern California Norris Comprehensive Cancer Center
  • Centre Léon Bérard
  • CRNS Institut Curie
  • University Hospital
  • Ambry Genetics Corporation
  • University of Pennsylvania
  • United States and Europe
  • Universität Leipzig
  • University of Manchester
  • National Center for Scientific Research (NCSR) «Demokritos»
  • Dana-Farber Cancer Institute
  • Mayo Clinic
  • Beckman Research Institute of City of Hope
  • Universität zu Köln
  • University Hospital of Cologne
  • Sylvester Comprehensive Cancer Center
  • Vilniaus universitetas
  • State Research Institute Innovative Medicine Center
  • Charles University and General University Hospital in Prague
  • Univerzita Karlova
  • Yong Loo Lin School of Medicine
  • Duke-NUS Medical School
  • PSL University
  • Ita-Suomen yliopisto
  • Fondazione IRCCS Istituto Nazionale Dei Tumori
  • University of California Irvine
  • University of Vermont College of Medicine
  • Center for Nano-Science
  • University of Toronto
  • University of Malaya
  • Oulu University Hospital
  • Cancer Research Malaysia
  • University of Melbourne
  • Southern Health Care Network
  • University of Chicago
  • Kepler University Hospital Linz
  • Università degli Studi di Roma La Sapienza
  • Medizinische Hochschule Hannover
  • Faculty of Information Technology and Electrical Engineering
  • University of New South Wales Sydney
  • Garvan Institute of Medical Research
  • Princess Anne Hospital
  • University of Miami Leonard M. Miller School of Medicine
  • Aarhus University Hospital
  • Papa Giovanni XXIII Hospital
  • Peter MacCallum Cancer Center
  • Rigshospitalet
  • Huntsman Cancer Institute
  • Melbourne School of Population and Global Health
  • QIMR Berghofer Medical Research Institute
  • F76000 and Normandy University
  • Centre Hospitalier de l'Université de Montréal
  • Department of Clinical Genetics and Pathology
  • Department of Laboratory Medicine
  • Office for Medical Services
  • Lunds Universitet
  • IFOM-The FIRC Institute for Molecular Oncology
  • Vanderbilt-Ingram Cancer Center
  • McGill University

Research output: Contribution to journal › Article › peer-review

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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 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
Pages (from-to)674-685
Number of pages12
JournalJournal of clinical oncology
Volume38
Issue number7
Early online date16 Dec 2019
DOIs
Publication statusPublished - 1 Mar 2020

Funding

The City of Hope Clinical Cancer Genomics Community Research Network was supported by award number RC4A153828 (principal investigator, J.N.W.) from the National Cancer Institute (NCI) and the Office of the Director, National Institutes of Health (NIH). J.N.W. was also supported by the Breast Cancer Research Foundation and the Dr Norman & Melinda Payson Professorship in Medical Oncology. T.S. was supported by the NCI grant K08CA234394. A.M.D. is supported by Cancer Research UK grant C8197/A16565. The HEBCS study was supported by a Helsinki University Hospital research grant, the Sigrid Jusélius Foundation, and the Finnish Cancer Society. K.B.M.C. is supported by grant G.A044.10 from the Fund for Scientific Research–Flanders. SWE-BRCA (The Swedish BRCA1 & BRCA2 Study Collaborators): Gothenburg, Sahlgrenska University Hospital: Zakaria Einbeigi; Linköping University Hospital: Marie Stenmark-Askmalm and Ekaterina Kuchinskaya; Lund University Hospital: Hans Ehrencrona, Therese Törngren, Anders Kvist, and Åke Borg; Stockholm, Karolinska University Hospital: Brita Arver, Annika Lindblom, and Emma Tham; Umeå University Hospital: Beatrice Melin; and Uppsala University Hospital: Ylva Paulsson-Karlsson. Z.K., P.K., J.S., and M.J. were supported by grants from the Ministry of Health of the Czech Republic (NV16-29959A) and Charles University projects PROGRES Q28/LF1 and SVV2019/260367. We thank clinical geneticists Kamila Vesela, Ales Panczak, and Jaroslav Kotlas from the Institute of Biology and Medical Genetics and Michal Vocka from the Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital in Prague for their valuable contribution to the study. This study was supported by Research Council of Lithuania grant SEN18/2015. A.S.G.L. was supported by grants from the National Medical Research Council (NMRC) of Singapore (NMRC/0763/2003, NMRC/1194/2008, NMRC/CBRG/0034/2013). S.N. is partially supported by the Morris and Horowitz Families Endowed Professorship. P.C. and J.L.B. represent the WECARE Study Collaborative Group, which is supported by NCI grants CA083178, CA097397, CA114236, and CA129639. S.D. is funded by Susan G Komen. F.C. was supported by NIH grants CA128978 and CA116167, an NIH Specialized Program of Research Excellence in Breast Cancer grant (CA116201), and the Breast Cancer Research Foundation. This study was partially supported by grants from Associazione Italiana per la Ricerca sul Cancro to P.Pe. (AIRC-IG #4017) and P.R. (AIRC-IG #15547) and from Ricerca Finalizzata–Bando 2010 from Ministero della Salute, Italy (C.T. and P.Pe.), and by funds from the Italian citizens who allocated a 5/1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori according to Italian laws (INT-Institutional Strategic Projects “5x1000”; S.M.). L.O. was supported by Associazione Italiana per la Ricerca sul Cancro grant AIRC-IG 2018-ID. 21389 and Italian Ministry of Education, Universities and Research–Dipartimenti di Eccellenza-L. 232/2016. D.G.E. is supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215–20007). We thank all the collaborating cancer clinics of the French National Study GENESIS (GENE SISters); the GENESIS principal investigators D. Stoppa-Lyonnet and N. Andrieu; the Investigation Platform (PIGE), S. Eon-Marchais, M.G. Dondon, D. Le Gal, J. Beauvallet, N. Mebirouk, and E. Cavaciuti; as well as L. Barjhoux (Biological Resource Centre). The GENESIS study was supported by the Ligue Nationale Contre le Cancer (grants PRE05/DSL and PRE07/DSL), the Institut National du Cancer (INCa grant No. b2008-029/LL-LC), and the Site de Recherche Intégrée sur le Cancer (grant INCa-DGOS-4654). E.R.M. acknowledges funding from the European Research Council (Advanced Researcher Award), NIHR (Senior Investigator Award and Cambridge NIHR Biomedical Research Centre), and Cancer Research UK Cambridge Cancer Centre. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health. The University of Cambridge has received salary support for E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. We thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from National Health and Medical Research Council (NHMRC), the National Breast Cancer Foundation, Cancer Australia, and NIH) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by a grant from the National Breast Cancer Foundation and previously by NHMRC; the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. We thank the Breast Cancer Family Registry (BCFR), which is funded by the NCI, NIH. T.N.-D. is supported by a Career Development Fellowship from the National Breast Cancer Foundation (Australia, ECF-17-001). We thank Eric Rosenthal and the team at Myriad Genetics for their help in recruiting patients. This work was supported by NCI grant UM1 CA164920. The content of this article does not necessarily reflect the views or policies of the NCI or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government or the BCFR. I.L.A. holds the Anne and Max Tanenbaum Chair in Molecular Medicine at Mount Sinai Hospital and the University of Toronto. The Australian site of the BCFR was also supported by the NHMRC of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation, and the Victorian Breast Cancer Research Consortium. This work was also supported by the NHMRC (project grant APP1029974) and the Victorian Breast Cancer Research Consortium. M.So. is an NHMRC Senior Research Fellow, and J.L.H. is an NHMRC Senior Principal Research Fellow. T.P. is supported in part by the Ingram Professorship and the Kleeberg Foundation. R.W. is supported by the Academy of Finland (project grant 318337 and Center of Excellence grant 251314), the Finnish Cancer Foundation, the Sigrid Jusélius Foundation, the University of Oulu, and the special Government Funding of Oulu University Hospital grants. K.Py. is supported by Academy of Finland Research Fellow grant 314183 and the Finnish Cancer Foundation. A.Ma. is supported by special Government Funding of Kuopio University Hospital grants, the Cancer Fund of North Savo, the Finnish Cancer Foundation, and the strategic funding of the University of Eastern Finland. The MyBrCa study was funded by research grants from the Wellcome trust (203477/Z/16/Z), Ministry of Higher Education to University Malaya (UM.c/Hir/MOHe/06), Estée Lauder group of companies, Sime Darby Foundation, PETRONAS Foundation, Cancer Research UK (c1287/a16563, c8197/a16565, and c12292/a20861), and the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement 634935 (BriDgeS), and the PerSPectiVe project was funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Genome Québec, and the Quebec Breast Cancer Foundation. The University of Miami Caribbean Women’s Cancer Study was funded by the Susan G Komen Foundation. P.P. receives salary support from the National Health Service (NHS) in the East of England through the Clinical Academic Reserve. S.H.L.G. is funded by the CDMRP Ovarian Cancer program (W81XWH-18-1-0072). J.B. was supported by the Carlos III National Health Institute funded by FEDER funds–a way to build Europe (PI16/11363). W.D.F. is funded by Susan G Komen and CIHR Foundation Grant FDN 148390. The analysis and data management for this project was support by Cancer Research UK grant C12292/A20861. M.T. was funded by the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement n.310018.

FundersFunder number
Breast Cancer Family Registry
Cancer Councils of New South Wales
Cancer Foundation of Western Australia
Cancer Fund of North Savo
Cancer Research UK Cambridge Centre
Carlos III National Health Institute
Center of Excellence for Ecoinformatics, School of Management, Walailak University, Thailand251314
Finnish Cancer SocietyG.A044.10
Fund for Scientific Research–Flanders
Kleeberg Foundation
Ministry of Higher Education to University MalayaUM.c/Hir/MOHe/06
Morris and Horowitz Families EndowedCA097397, CA083178
Oulu University Hospital314183
PETRONAS Foundation
University of South Australia
Victorian Breast Cancer Research ConsortiumAPP1029974
National Institutes of Health
National Cancer InstituteR01CA116167, ECF-17-001, K08CA234394, R01CA114236, R01CA129639, UM1 CA164920
National Institute of Environmental Health SciencesR01ES027121
Congressionally Directed Medical Research ProgramsW81XWH-18-1-0072
Office of the Director
Breast Cancer Research Foundation
University of Miami
Univerzita Karlova v PrazeSVV2019/260367, PROGRES Q28/LF1
University of Eastern Finland
Helsingin ja Uudenmaan Sairaanhoitopiiri
Genome Canada
Susan G. KomenCA116201, CA128978
Wellcome Trust203477/Z/16/Z
Horizon 2020 Framework Programme634935
Seventh Framework ProgrammeFP/2007-2013
Génome Québec
Ministère de l'Économie, de la Science et de l'Innovation - Québec
Manchester Biomedical Research CentreIS-BRC-1215–20007
Fondation du cancer du sein du Québec
Yayasan Sime Darby
Government of Canada
Canadian Institutes of Health ResearchFDN 148390
National Institute for Health and Care Research
Cancer Research UKc12292/a20861, C8197/A16565, c8197/a16565
European Research Council310018
University College Birmingham
National Breast Cancer Foundation
Cancer Council NSW
Cancer Australia
Cancer Council Queensland
VicHealth
University College BirminghamNMRC/CBRG/0034/2013, NMRC/1194/2008, NMRC/0763/2003
Academy of Finland318337
Ministerstvo Zdravotnictví Ceské RepublikyNV16-29959A
Kuopion Yliopistollinen Sairaala
Ligue Contre le CancerPRE05/DSL, PRE07/DSL
Lietuvos Mokslo TarybaSEN18/2015
Associazione Italiana per la Ricerca sul Cancro
Oulun yliopisto
Sigrid Juséliuksen Säätiö
Institut National Du CancerINCa-DGOS-4654, b2008-029/LL-LC
Syöpäjärjestöt
European Regional Development FundPI16/11363
Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"AIRC-IG 2018-ID

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