Genome Medicine (May 2022)
Breast cancer risks associated with missense variants in breast cancer susceptibility genes
- Leila Dorling,
- Sara Carvalho,
- Jamie Allen,
- Michael T. Parsons,
- Cristina Fortuno,
- Anna González-Neira,
- Stephan M. Heijl,
- Muriel A. Adank,
- Thomas U. Ahearn,
- Irene L. Andrulis,
- Päivi Auvinen,
- Heiko Becher,
- Matthias W. Beckmann,
- Sabine Behrens,
- Marina Bermisheva,
- Natalia V. Bogdanova,
- Stig E. Bojesen,
- Manjeet K. Bolla,
- Michael Bremer,
- Ignacio Briceno,
- Nicola J. Camp,
- Archie Campbell,
- Jose E. Castelao,
- Jenny Chang-Claude,
- Stephen J. Chanock,
- Georgia Chenevix-Trench,
- NBCS Collaborators,
- J. Margriet Collée,
- Kamila Czene,
- Joe Dennis,
- Thilo Dörk,
- Mikael Eriksson,
- D. Gareth Evans,
- Peter A. Fasching,
- Jonine Figueroa,
- Henrik Flyger,
- Marike Gabrielson,
- Manuela Gago-Dominguez,
- Montserrat García-Closas,
- Graham G. Giles,
- Gord Glendon,
- Pascal Guénel,
- Melanie Gündert,
- Andreas Hadjisavvas,
- Eric Hahnen,
- Per Hall,
- Ute Hamann,
- Elaine F. Harkness,
- Mikael Hartman,
- Frans B. L. Hogervorst,
- Antoinette Hollestelle,
- Reiner Hoppe,
- Anthony Howell,
- kConFab Investigators,
- SGBCC Investigators,
- Anna Jakubowska,
- Audrey Jung,
- Elza Khusnutdinova,
- Sung-Won Kim,
- Yon-Dschun Ko,
- Vessela N. Kristensen,
- Inge M. M. Lakeman,
- Jingmei Li,
- Annika Lindblom,
- Maria A. Loizidou,
- Artitaya Lophatananon,
- Jan Lubiński,
- Craig Luccarini,
- Michael J. Madsen,
- Arto Mannermaa,
- Mehdi Manoochehri,
- Sara Margolin,
- Dimitrios Mavroudis,
- Roger L. Milne,
- Nur Aishah Mohd Taib,
- Kenneth Muir,
- Heli Nevanlinna,
- William G. Newman,
- Jan C. Oosterwijk,
- Sue K. Park,
- Paolo Peterlongo,
- Paolo Radice,
- Emmanouil Saloustros,
- Elinor J. Sawyer,
- Rita K. Schmutzler,
- Mitul Shah,
- Xueling Sim,
- Melissa C. Southey,
- Harald Surowy,
- Maija Suvanto,
- Ian Tomlinson,
- Diana Torres,
- Thérèse Truong,
- Christi J. van Asperen,
- Regina Waltes,
- Qin Wang,
- Xiaohong R. Yang,
- Paul D. P. Pharoah,
- Marjanka K. Schmidt,
- Javier Benitez,
- Bas Vroling,
- Alison M. Dunning,
- Soo Hwang Teo,
- Anders Kvist,
- Miguel de la Hoya,
- Peter Devilee,
- Amanda B. Spurdle,
- Maaike P. G. Vreeswijk,
- Douglas F. Easton
Affiliations
- Leila Dorling
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge
- Sara Carvalho
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge
- Jamie Allen
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge
- Michael T. Parsons
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute
- Cristina Fortuno
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute
- Anna González-Neira
- Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO)
- Stephan M. Heijl
- Bio-Prodict
- Muriel A. Adank
- Family Cancer Clinic, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital
- Thomas U. Ahearn
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health
- Irene L. Andrulis
- Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
- Päivi Auvinen
- Translational Cancer Research Area, University of Eastern Finland
- Heiko Becher
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf
- Matthias W. Beckmann
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU)
- Sabine Behrens
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ)
- Marina Bermisheva
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences
- Natalia V. Bogdanova
- Department of Radiation Oncology, Hannover Medical School
- Stig E. Bojesen
- Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital
- Manjeet K. Bolla
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge
- Michael Bremer
- Department of Radiation Oncology, Hannover Medical School
- Ignacio Briceno
- Medical Faculty, Universidad de La Sabana
- Nicola J. Camp
- Department of Internal Medicine and Huntsman Cancer Institute, University of Utah
- Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, The University of Edinburgh, Western General Hospital
- Jose E. Castelao
- Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS
- Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ)
- Stephen J. Chanock
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health
- Georgia Chenevix-Trench
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute
- NBCS Collaborators
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet
- J. Margriet Collée
- Department of Clinical Genetics, Erasmus University Medical Center
- Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Joe Dennis
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge
- Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School
- Mikael Eriksson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- D. Gareth Evans
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre
- Peter A. Fasching
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU)
- Jonine Figueroa
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health
- Henrik Flyger
- Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital
- Marike Gabrielson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Manuela Gago-Dominguez
- Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS,
- Montserrat García-Closas
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health
- Graham G. Giles
- Cancer Epidemiology Division, Cancer Council Victoria
- Gord Glendon
- Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital
- Pascal Guénel
- Team “Exposome and Heredity”, CESP, Inserm, Gustave Roussy, University Paris-Saclay, UVSQ
- Melanie Gündert
- Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ)
- Andreas Hadjisavvas
- Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics
- Eric Hahnen
- Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne
- Per Hall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Ute Hamann
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ)
- Elaine F. Harkness
- Nightingale & Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust
- Mikael Hartman
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Frans B. L. Hogervorst
- Family Cancer Clinic, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital
- Antoinette Hollestelle
- Department of Medical Oncology, Erasmus MC Cancer Institute
- Reiner Hoppe
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
- Anthony Howell
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre
- kConFab Investigators
- Research Department, Peter MacCallum Cancer Center
- SGBCC Investigators
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Anna Jakubowska
- Department of Genetics and Pathology, Pomeranian Medical University
- Audrey Jung
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ)
- Elza Khusnutdinova
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences
- Sung-Won Kim
- Department of Surgery, Daerim Saint Mary’s Hospital
- Yon-Dschun Ko
- Department of Internal Medicine, Johanniter GmbH Bonn
- Vessela N. Kristensen
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo
- Inge M. M. Lakeman
- Department of Human Genetics, Leiden University Medical Center
- Jingmei Li
- Department of Surgery, National University Health System
- Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet
- Maria A. Loizidou
- Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics
- Artitaya Lophatananon
- Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester
- Jan Lubiński
- Department of Genetics and Pathology, Pomeranian Medical University
- Craig Luccarini
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge
- Michael J. Madsen
- Department of Internal Medicine and Huntsman Cancer Institute, University of Utah
- Arto Mannermaa
- Translational Cancer Research Area, University of Eastern Finland
- Mehdi Manoochehri
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ)
- Sara Margolin
- Department of Oncology
- Dimitrios Mavroudis
- Department of Medical Oncology, University Hospital of Heraklion
- Roger L. Milne
- Cancer Epidemiology Division, Cancer Council Victoria
- Nur Aishah Mohd Taib
- Breast Cancer Research Unit, Faculty of Medicine, University Malaya Cancer Research Institute, University of Malaya
- Kenneth Muir
- Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester
- Heli Nevanlinna
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki
- William G. Newman
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre
- Jan C. Oosterwijk
- Department of Genetics, University Medical Center Groningen, University Groningen
- Sue K. Park
- Department of Preventive Medicine, Seoul National University College of Medicine
- Paolo Peterlongo
- Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology
- Paolo Radice
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori (INT)
- Emmanouil Saloustros
- Department of Oncology, University Hospital of Larissa
- Elinor J. Sawyer
- School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy’s Campus, King’s College London
- Rita K. Schmutzler
- Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne
- Mitul Shah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge
- Xueling Sim
- Saw Swee Hock School of Public Health, National University of Singapore and National University Health System
- Melissa C. Southey
- Cancer Epidemiology Division, Cancer Council Victoria
- Harald Surowy
- Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ)
- Maija Suvanto
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki
- Ian Tomlinson
- Institute of Cancer and Genomic Sciences, University of Birmingham
- Diana Torres
- Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ)
- Thérèse Truong
- Team “Exposome and Heredity”, CESP, Inserm, Gustave Roussy, University Paris-Saclay, UVSQ
- Christi J. van Asperen
- Department of Clinical Genetics, Leiden University Medical Center
- Regina Waltes
- Gynaecology Research Unit, Hannover Medical School
- Qin Wang
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge
- Xiaohong R. Yang
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health
- Paul D. P. Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge
- Marjanka K. Schmidt
- Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital
- Javier Benitez
- Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO)
- Bas Vroling
- Bio-Prodict
- Alison M. Dunning
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge
- Soo Hwang Teo
- Breast Cancer Research Unit, Faculty of Medicine, University Malaya Cancer Research Institute, University of Malaya
- Anders Kvist
- Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University
- Miguel de la Hoya
- Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos)
- Peter Devilee
- Department of Human Genetics, Leiden University Medical Center
- Amanda B. Spurdle
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute
- Maaike P. G. Vreeswijk
- Department of Human Genetics, Leiden University Medical Center
- Douglas F. Easton
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge
- DOI
- https://doi.org/10.1186/s13073-022-01052-8
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 17
Abstract
Abstract Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
Keywords
