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 Lee; 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

doi:10.1200/JCO.19.01907

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

Journal article

Open access

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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, …

Journal of clinical oncology, Vol.38(7), pp.674-685

2020-03-01

DOI: https://doi.org/10.1200/JCO.19.01907

PMID: 31841383

Abstract

Breast Neoplasms, Male - genetics

Genetic Predisposition to Disease

Age Factors

Fanconi Anemia Complementation Group N Protein - genetics

Humans

Middle Aged

Male

Pancreatic Neoplasms - genetics

Risk

Ovarian Neoplasms - genetics

Neoplasms - genetics

Internationality

Aged, 80 and over

Germ-Line Mutation

Adult

Female

Aged

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 pathogenic variants (PVs) because these risks have not been extensively characterized. We analyzed data from 524 families with 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. We found associations between PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; = 6.5 × 10 ), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; = 4.1 × 10 ), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; = 8.7 × 10 ), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; = 2.6 × 10 ). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( for trend = 2.0 × 10 ). 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 ( 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. These results confirm as a major breast cancer susceptibility gene and establish substantial associations between germline PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of into risk prediction models and optimize the clinical cancer risk management of PV carriers.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.189 Genome Studies; 1.189.597 BRCA1
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

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Title: Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families
Creators: Xin Yang - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Goska Leslie - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Alicja Doroszuk - Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
Sandra Schneider - Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
Jamie Allen - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Brennan Decker - Department of Pathology, Brigham and Women's Hospital, Boston, MA
Alison M Dunning - Centre for Cancer Genetic Epidemiology, Department of Oncology,University of Cambridge, Cambridge, United Kingdom
James Redman - Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
James Scarth - Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
Inga Plaskocinska - Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
Craig Luccarini - Centre for Cancer Genetic Epidemiology, Department of Oncology,University of Cambridge, Cambridge, United Kingdom
Mitul Shah - Centre for Cancer Genetic Epidemiology, Department of Oncology,University of Cambridge, Cambridge, United Kingdom
Karen Pooley - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Leila Dorling - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Andrew Lee - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Muriel A Adank - Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands
Julian Adlard - Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom
Kristiina Aittomäki - Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
Irene L Andrulis - Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada
Peter Ang - Laboratory of Molecular Oncology, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore
Julian Barwell - Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
Jonine L Bernstein - Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
Kristie Bobolis - Clinical Cancer Genomics Community Research Network, City of Hope, Duarte, CA
Åke Borg - Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
Carl Blomqvist - Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
Kathleen B M Claes - Centre for Medical Genetics, Ghent University, Ghent, Belgium
Patrick Concannon - University of Florida Genetics Institute, University of Florida, Gainesville, FL
Adeline Cuggia - The Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
Julie O Culver - Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA
Francesca Damiola - Biopathologie, Centre Léon Bérard, Lyon, France
Antoine de Pauw - Service de Génétique, Institut Curie, Paris, France
Orland Diez - Oncogenetics Group, Clinical and Molecular Genetics Area, Vall d'Hebron Institute of Oncology (VHIO), University Hospital, Vall d'Hebron, Barcelona, Spain
Jill S Dolinsky - Ambry Genetics, Aliso Viejo, CA
Susan M Domchek - Prospective Registry of Multiplex Testing (PROMPT), United States and Europe
Christoph Engel - Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
D Gareth Evans - 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
Florentia Fostira - Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos," Athens, Greece
Judy Garber - Dana-Farber Cancer Institute, Boston, MA
Lisa Golmard - Service de Génétique, Institut Curie, Paris, France
Ellen L Goode - Department of Health Sciences Research, Mayo Clinic, Rochester, MN
Stephen B Gruber - City of Hope National Medical Center, Duarte, CA
Eric Hahnen - Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany
Christopher Hake - Clinical Cancer Genomics Community Research Network, City of Hope, Duarte, CA
Tuomas Heikkinen - Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
Judith E Hurley - Division of Medical Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL
Ramunas Janavicius - State Research Institute Innovative Medicine Center, Vilnius, Lithuania
Zdenek Kleibl - Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Petra Kleiblova - Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
Irene Konstantopoulou - Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos," Athens, Greece
Anders Kvist - Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
Holly Laduca - Ambry Genetics, Aliso Viejo, CA
Ann S G Lee - SingHealth Duke-NUS Oncology Academic Clinical Programme (ONCO ACP), Duke-NUS Medical School, Singapore
Fabienne Lesueur - INSERM U900, Institut Curie, PSL University, Mines ParisTech, Paris, France
Eamonn R Maher - Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
Arto Mannermaa - Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland
Siranoush Manoukian - Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Rachel McFarland - Department of Epidemiology, University of California, Irvine, Irvine, CA
Wendy McKinnon - Familial Cancer Program, The University of Vermont Cancer Center, Burlington, VT
Alfons Meindl - Department of Gynecology and Obstetrics, Ludwig-Maximilians University of Munich, Munich, Germany
Kelly Metcalfe - Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Ontario, Canada
Nur Aishah Mohd Taib - University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
Jukka Moilanen - Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu, Finland
Katherine L Nathanson - Department ofMedicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
Susan Neuhausen - Department of Population Sciences, Beckman Research Institute, City of Hope, Duarte, CA
Pei Sze Ng - Cancer Research Malaysia, Subang Jaya Selangor, Malaysia
Tu Nguyen-Dumont - Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
Sarah M Nielsen - Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL
Florian Obermair - Institute of Medical Genetics, Kepler University Hospital Linz and Laboratory for Molecular Biology and Tumor Cytogenetics, Ordensklinikum Linz, Linz, Austria
Kenneth Offit - Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Olufunmilayo I Olopade - Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL
Laura Ottini - Department of Molecular Medicine, University La Sapienza, Rome, Italy
Judith Penkert - Department of Human Genetics, Hannover Medical School, Hannover, Germany
Katri Pylkäs - 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
Paolo Radice - Unit of Molecular Basis of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Susan J Ramus - The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
Vilius Rudaitis - Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania
Lucy Side - Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom
Rachel Silva-Smith - Department of Genetics, University of MiamiMiller School of Medicine, Miami, FL
Valentina Silvestri - Department of Molecular Medicine, University La Sapienza, Rome, Italy
Anne-Bine Skytte - Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
Thomas Slavin - Department of Medical Oncology, Division of Clinical Cancer Genomics, City of Hope, Duarte, CA
Jana Soukupova - Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Carlo Tondini - Unit of Medical Oncology, Department of Oncology and Hematology,Papa Giovanni XXIII Hospital, Bergamo, Italy
Alison H Trainer - Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
Gary Unzeitig - Clinical Cancer Genomics Community Research Network, City of Hope, Duarte, CA
Lydia Usha - Clinical Cancer Genomics Community Research Network, City of Hope, Duarte, CA
Thomas van Overeem Hansen - Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
James Whitworth - Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
Marie Wood - Familial Cancer Program, The University of Vermont Cancer Center, Burlington, VT
Cheng Har Yip - Cancer Research Malaysia, Subang Jaya Selangor, Malaysia
Sook-Yee Yoon - Cancer Research Malaysia, Subang Jaya Selangor, Malaysia
Amal Yussuf - Ambry Genetics, Aliso Viejo, CA
George Zogopoulos - The Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada
David Goldgar - Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT
John L Hopper - Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
Georgia Chenevix-Trench - Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
Paul Pharoah - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Sophia H L George - Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL
Judith Balmaña - Prospective Registry of Multiplex Testing (PROMPT), United States and Europe
Claude Houdayer - Genetics Department, F76000 and Normandy University, UNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Rouen University Hospital, Rouen, France
Paul James - Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
Zaki El-Haffaf - Department of Genetics, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
Hans Ehrencrona - Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
Marketa Janatova - Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
Paolo Peterlongo - Genome Diagnostics Program, IFOM-The FIRC Institute for Molecular Oncology, Milan, Italy
Heli Nevanlinna - Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
Rita Schmutzler - Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany
Soo-Hwang Teo - Cancer Research Malaysia, Subang Jaya Selangor, Malaysia
Mark Robson - Breast Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Tuya Pal - Vanderbilt-Ingram Cancer Center, Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
Fergus Couch - Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
Jeffrey N Weitzel - Department of Medical Oncology, Division of Clinical Cancer Genomics, City of Hope, Duarte, CA
Aaron Elliott - Ambry Genetics, Aliso Viejo, CA
Melissa Southey - Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
Robert Winqvist - 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
Douglas F Easton - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
William D Foulkes - Departments of Human Genetics, Oncology, and Medicine, McGill University, Montreal, Quebec, Canada
Antonis C Antoniou - Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Marc Tischkowitz - Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom
Publication Details: Journal of clinical oncology, Vol.38(7), pp.674-685
Publisher: United States
Grant note: R01 CA129639 / NCI NIH HHS Wellcome Trust U01 CA083178 / NCI NIH HHS P50 CA116201 / NCI NIH HHS R01 CA116167 / NCI NIH HHS 10119 / Cancer Research UK UM1 CA164920 / NCI NIH HHS P30 CA008748 / NCI NIH HHS U01 CA116167 / NCI NIH HHS R01 CA114236 / NCI NIH HHS L60 MD014321 / NIMHD NIH HHS R01 ES027121 / NIEHS NIH HHS R01 CA128978 / NCI NIH HHS 203477/Z/16/Z / Wellcome Trust 10124 / Cancer Research UK R01 CA097397 / NCI NIH HHS K08 CA234394 / NCI NIH HHS
Academic Unit: Miller School of Medicine; UMMG Dept of Medicine - Hematology/Oncology; UMMG Dept of Obstetrics & Gynecology
Language: English
Resource Type: Journal article
PMID: 31841383
Record Identifier: 991031576397102976