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.

Ambry Genetics Aliso Viejo CA

Biopathologie Centre Léon Bérard Lyon France

Breast Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Cancer Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda MD

Cancer Research Malaysia Subang Jaya Selangor Malaysia

Center for Clinical Cancer Genetics The University of Chicago Chicago IL

Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Center for Hereditary Breast and Ovarian Cancer University Hospital of Cologne Cologne Germany

Center for Molecular Medicine Cologne University of Cologne Cologne Germany

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge United Kingdom

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia

Centre for Medical Genetics Ghent University Ghent Belgium

City of Hope National Medical Center Duarte CA

Clinical Cancer Genomics Community Research Network City of Hope Duarte CA

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York NY

Dana Farber Cancer Institute Boston MA

Department of Clinical Genetics Aarhus University Hospital Aarhus Denmark

Department of Clinical Genetics and Pathology Department of Laboratory Medicine Office for Medical Services Lund Sweden

Department of Clinical Genetics Helsinki University Hospital University of Helsinki Helsinki Finland

Department of Clinical Genetics Oulu University Hospital Medical Research Center Oulu and PEDEGO Research Unit University of Oulu Oulu Finland

Department of Clinical Genetics Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Pathology The University of Melbourne Melbourne Victoria Australia

Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY

Department of Epidemiology University of California Irvine Irvine CA

Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Department of Genetics Centre Hospitalier de l'Université de Montréal Montreal Quebec Canada

Department of Genetics University of MiamiMiller School of Medicine Miami FL

Department of Gynecology and Obstetrics Ludwig Maximilians University of Munich Munich Germany

Department of Health Sciences Research Mayo Clinic Rochester MN

Department of Human Genetics Hannover Medical School Hannover Germany

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN

Department of Medical Genetics NIHR Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre University of Cambridge Cambridge United Kingdom

Department of Medical Oncology Division of Clinical Cancer Genomics City of Hope Duarte CA

Department of Molecular Medicine University La Sapienza Rome Italy

Department of Obstetrics and Gynecology Helsinki University Hospital University of Helsinki Helsinki Finland

Department of Obstetrics Gynecology and Reproductive Sciences Division of Gynecologic Oncology Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine Miami FL

Department of Oncology Helsinki University Hospital University of Helsinki Helsinki Finland

Department of Pathology Brigham and Women's Hospital Boston MA

Department of Physiology Yong Loo Lin School of Medicine National University of Singapore Singapore

Department of Population Sciences Beckman Research Institute City of Hope Duarte CA

Department ofMedicine Abramson Cancer Center Perelman School of Medicine University of Pennsylvania Philadelphia PA

Departments of Human Genetics Oncology and Medicine McGill University Montreal Quebec Canada

Division of Clinical Genetics Department of Laboratory Medicine Lund University Lund Sweden

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

Division of Medical Oncology Sylvester Comprehensive Cancer Center University of Miami Miller School of Medicine Miami FL

Division of Oncology and Pathology Department of Clinical Sciences Lund Lund University Lund Sweden

Familial Cancer Program The University of Vermont Cancer Center Burlington VT

Family Cancer Clinic The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam the Netherlands

Genetics Department F76000 and Normandy University UNIROUEN INSERM U1245 Normandy Centre for Genomic and Personalized Medicine Rouen University Hospital Rouen France

Genome Diagnostics Program IFOM The FIRC Institute for Molecular Oncology Milan Italy

Hematology Oncology and Transfusion Medicine Center Department of Molecular and Regenerative Medicine Vilnius University Hospital Santariskiu Clinics Vilnius Lithuania

Huntsman Cancer Institute Department of Population Health Sciences University of Utah Salt Lake City UT

INSERM U900 Institut Curie PSL University Mines ParisTech Paris France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany

Institute of Biochemistry and Experimental Oncology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Clinical Medicine Pathology and Forensic Medicine University of Eastern Finland Kuopio Finland

Institute of Medical Genetics Kepler University Hospital Linz and Laboratory for Molecular Biology and Tumor Cytogenetics Ordensklinikum Linz Linz Austria

Keck School of Medicine University of Southern California Norris Comprehensive Cancer Center Los Angeles CA

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

Laboratory of Molecular Oncology Division of Cellular and Molecular Research National Cancer Centre Singapore Singapore

Lawrence S Bloomberg Faculty of Nursing University of Toronto Toronto Ontario Canada

Leicestershire Clinical Genetics Service University Hospitals of Leicester NHS Trust Leicester United Kingdom

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Toronto Ontario Canada

Molecular Diagnostics Laboratory INRASTES National Centre for Scientific Research Demokritos Athens Greece

Oncogenetics Group Clinical and Molecular Genetics Area Vall d'Hebron Institute of Oncology University Hospital Vall d'Hebron Barcelona Spain

Parkville Familial Cancer Centre Peter MacCallum Cancer Center Melbourne Victoria Australia

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton Victoria Australia

Prospective Registry of Multiplex Testing United States and Europe

School of Women's and Children's Health Faculty of Medicine University of New South Wales Sydney Sydney New South Wales Australia

Service de Génétique Institut Curie Paris France

SingHealth Duke NUS Oncology Academic Clinical Programme Duke NUS Medical School Singapore

Sir Peter MacCallum Department of Oncology The University of Melbourne Melbourne Victoria Australia

State Research Institute Innovative Medicine Center Vilnius Lithuania

The Goodman Cancer Research Centre McGill University Montreal Quebec Canada

The Kinghorn Cancer Centre Garvan Institute of Medical Research Sydney New South Wales Australia

The Research Institute of the McGill University Health Centre McGill University Montreal Quebec Canada

Unit of Medical Genetics Department of Medical Oncology and Hematology Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Unit of Medical Oncology Department of Oncology and Hematology Papa Giovanni XXIII Hospital Bergamo Italy

Unit of Molecular Basis of Genetic Risk and Genetic Testing Department of Research Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

University Malaya Cancer Research Institute Faculty of Medicine University Malaya Kuala Lumpur Malaysia

University of Florida Genetics Institute University of Florida Gainesville FL

Vanderbilt Ingram Cancer Center Division of Genetic Medicine Department of Medicine Vanderbilt University Medical Center Nashville TN

Wessex Clinical Genetics Service Princess Anne Hospital Southampton United Kingdom

Yorkshire Regional Genetics Service Chapel Allerton Hospital Leeds United Kingdom

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