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Breast cancer risks associated with missense variants in breast cancer susceptibility genes.

About this Publication
Title
Breast cancer risks associated with missense variants in breast cancer susceptibility genes.
Pubmed ID
35585550 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Genome Med. 2022 May 18; Volume 14 (Issue 1): Pages 51
Authors
Dorling L , Carvalho S , Allen J , Parsons MT , Fortuno C , González-Neira A , Heijl SM , Adank MA , Ahearn TU , Andrulis IL , Auvinen P , Becher H , Beckmann MW , Behrens S , Bermisheva M , Bogdanova NV , Bojesen SE , Bolla MK , Bremer M , Briceno I , ...show more Camp NJ , Campbell A , Castelao JE , Chang-Claude J , Chanock SJ , Chenevix-Trench G , NBCS Collaborators , Collée JM , Czene K , Dennis J , Dörk T , Eriksson M , Evans DG , Fasching PA , Figueroa J , Flyger H , Gabrielson M , Gago-Dominguez M , García-Closas M , Giles GG , Glendon G , Guénel P , Gündert M , Hadjisavvas A , Hahnen E , Hall P , Hamann U , Harkness EF , Hartman M , Hogervorst FBL , Hollestelle A , Hoppe R , Howell A , kConFab Investigators , SGBCC Investigators , Jakubowska A , Jung A , Khusnutdinova E , Kim SW , Ko YD , Kristensen VN , Lakeman IMM , Li J , Lindblom A , Loizidou MA , Lophatananon A , Lubiński J , Luccarini C , Madsen MJ , Mannermaa A , Manoochehri M , Margolin S , Mavroudis D , Milne RL , Mohd Taib NA , Muir K , Nevanlinna H , Newman WG , Oosterwijk JC , Park SK , Peterlongo P , Radice P , Saloustros E , Sawyer EJ , Schmutzler RK , Shah M , Sim X , Southey MC , Surowy H , Suvanto M , Tomlinson I , Torres D , Truong T , van Asperen CJ , Waltes R , Wang Q , Yang XR , Pharoah PDP , Schmidt MK , Benitez J , Vroling B , Dunning AM , Teo SH , Kvist A , de la Hoya M , Devilee P , Spurdle AB , Vreeswijk MPG , Easton DF
Affiliations
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
  • Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
  • Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.
  • Bio-Prodict, Nijmegen, The Netherlands.
  • Family Cancer Clinic, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
  • Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20850, USA.
  • Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada.
  • Translational Cancer Research Area, University of Eastern Finland, 70210, Kuopio, Finland.
  • Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
  • Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg (FAU), 91054, Erlangen, Germany.
...show more
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, 450054, Russia.
  • Department of Radiation Oncology, Hannover Medical School, 30625, Hannover, Germany.
  • Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
  • Medical Faculty, Universidad de La Sabana, 140013, Bogota, Colombia.
  • Department of Internal Medicine and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
  • Centre for Genomic and Experimental Medicine, Institute of Genetics & Cancer, The University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, UK.
  • Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, 36312, Vigo, Spain.
  • Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, 3015 CN, The Netherlands.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 65, Stockholm, Sweden.
  • Gynaecology Research Unit, Hannover Medical School, 30625, Hannover, Germany.
  • Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
  • Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730, Herlev, Denmark.
  • Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, , 15706, Santiago de Compostela, Spain.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia.
  • Team "Exposome and Heredity", CESP, Inserm, Gustave Roussy, University Paris-Saclay, UVSQ, Villejuif, France.
  • Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology & Genetics, 2371, Nicosia, Cyprus.
  • Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
  • Nightingale & Genesis Prevention Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, M23 9LT, UK.
  • Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, 117549, Singapore.
  • Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, 3015 GD, The Netherlands.
  • Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376, Stuttgart, Germany.
  • NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
  • Department of Genetics and Pathology, Pomeranian Medical University, 71-252, Szczecin, Poland.
  • Department of Surgery, Daerim Saint Mary's Hospital, Seoul, 07442, Korea.
  • Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, 53113, Bonn, Germany.
  • Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450, Oslo, Norway.
  • Department of Human Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
  • Department of Surgery, National University Health System, Singapore, 119228, Singapore.
  • Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden.
  • Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PL, UK.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
  • Department of Oncology, 118 83, Södersjukhuset, Stockholm, Sweden.
  • Department of Medical Oncology, University Hospital of Heraklion, 711 10, Heraklion, Greece.
  • Breast Cancer Research Unit, Faculty of Medicine, University Malaya Cancer Research Institute, University of Malaya, 50603, Kuala Lumpur, Malaysia.
  • Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, 00290, Helsinki, Finland.
  • Department of Genetics, University Medical Center Groningen, University Groningen, Groningen, 9713 GZ, The Netherlands.
  • Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea.
  • Genome Diagnostics Program, IFOM - the FIRC Institute of Molecular Oncology, 20139, Milan, Italy.
  • Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori (INT), 20133, Milan, Italy.
  • Department of Oncology, University Hospital of Larissa, 411 10, Larissa, Greece.
  • School of Cancer & Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London, UK.
  • Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
  • Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, The Netherlands.
  • Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni Van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
  • Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, 22381, Lund, Sweden.
  • Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), 28040, Madrid, Spain.
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK. dfe20@medschl.cam.ac.uk.
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.

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