Cancers (Jul 2022)
Uncovering the Contribution of Moderate-Penetrance Susceptibility Genes to Breast Cancer by Whole-Exome Sequencing and Targeted Enrichment Sequencing of Candidate Genes in Women of European Ancestry
- Martine Dumont,
- Nana Weber-Lassalle,
- Charles Joly-Beauparlant,
- Corinna Ernst,
- Arnaud Droit,
- Bing-Jian Feng,
- Stéphane Dubois,
- Annie-Claude Collin-Deschesnes,
- Penny Soucy,
- Maxime Vallée,
- Frédéric Fournier,
- Audrey Lemaçon,
- Muriel A. Adank,
- Jamie Allen,
- Janine Altmüller,
- Norbert Arnold,
- Margreet G. E. M. Ausems,
- Riccardo Berutti,
- Manjeet K. Bolla,
- Shelley Bull,
- Sara Carvalho,
- Sten Cornelissen,
- Michael R. Dufault,
- Alison M. Dunning,
- Christoph Engel,
- Andrea Gehrig,
- Willemina R. R. Geurts-Giele,
- Christian Gieger,
- Jessica Green,
- Karl Hackmann,
- Mohamed Helmy,
- Julia Hentschel,
- Frans B. L. Hogervorst,
- Antoinette Hollestelle,
- Maartje J. Hooning,
- Judit Horváth,
- M. Arfan Ikram,
- Silke Kaulfuß,
- Renske Keeman,
- Da Kuang,
- Craig Luccarini,
- Wolfgang Maier,
- John W. M. Martens,
- Dieter Niederacher,
- Peter Nürnberg,
- Claus-Eric Ott,
- Annette Peters,
- Paul D. P. Pharoah,
- Alfredo Ramirez,
- Juliane Ramser,
- Steffi Riedel-Heller,
- Gunnar Schmidt,
- Mitul Shah,
- Martin Scherer,
- Antje Stäbler,
- Tim M. Strom,
- Christian Sutter,
- Holger Thiele,
- Christi J. van Asperen,
- Lizet van der Kolk,
- Rob B. van der Luijt,
- Alexander E. Volk,
- Michael Wagner,
- Quinten Waisfisz,
- Qin Wang,
- Shan Wang-Gohrke,
- Bernhard H. F. Weber,
- Genome of the Netherlands Project,
- GHS Study Group,
- Peter Devilee,
- Sean Tavtigian,
- Gary D. Bader,
- Alfons Meindl,
- David E. Goldgar,
- Irene L. Andrulis,
- Rita K. Schmutzler,
- Douglas F. Easton,
- Marjanka K. Schmidt,
- Eric Hahnen,
- Jacques Simard
Affiliations
- Martine Dumont
- Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada
- Nana Weber-Lassalle
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
- Charles Joly-Beauparlant
- Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada
- Corinna Ernst
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
- Arnaud Droit
- Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada
- Bing-Jian Feng
- Department of Dermatology, University of Utah, Salt Lake City, UT 84103, USA
- Stéphane Dubois
- Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada
- Annie-Claude Collin-Deschesnes
- Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada
- Penny Soucy
- Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada
- Maxime Vallée
- Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada
- Frédéric Fournier
- Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada
- Audrey Lemaçon
- Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada
- Muriel A. Adank
- Family Cancer Clinic, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands
- Jamie Allen
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Janine Altmüller
- Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
- Norbert Arnold
- Institute of Clinical Molecular Biology, Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, 24105 Kiel, Germany
- Margreet G. E. M. Ausems
- Division Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Center Utrecht, 3584 Utrecht, The Netherlands
- Riccardo Berutti
- Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany
- Manjeet K. Bolla
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Shelley Bull
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada
- Sara Carvalho
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Sten Cornelissen
- Division of Molecular Pathology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands
- Michael R. Dufault
- Precision Medicine and Computational Biology, Sanofi Genzyme, Cambridge, MA 02142, USA
- Alison M. Dunning
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
- Christoph Engel
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany
- Andrea Gehrig
- Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University of Würzburg, 97074 Würzburg, Germany
- Willemina R. R. Geurts-Giele
- Department of Clinical Genetics, Erasmus University Medical Center, 3015 Rotterdam, The Netherlands
- Christian Gieger
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Jessica Green
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada
- Karl Hackmann
- Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
- Mohamed Helmy
- The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
- Julia Hentschel
- Institute of Human Genetics, University Leipzig, 04103 Leipzig, Germany
- Frans B. L. Hogervorst
- Family Cancer Clinic, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands
- Antoinette Hollestelle
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands
- Maartje J. Hooning
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands
- Judit Horváth
- Institute of Human Genetics, University of Münster, 48149 Münster, Germany
- M. Arfan Ikram
- Department of Epidemiology, Erasmus MC University Medical Center, 3015 Rotterdam, The Netherlands
- Silke Kaulfuß
- Institute of Human Genetics, University Medical Center Göttingen, 37075 Göttingen, Germany
- Renske Keeman
- Division of Molecular Pathology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands
- Da Kuang
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
- Craig Luccarini
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
- Wolfgang Maier
- German Center for Neurodegenerative Diseases (DZNE), Department of Neurodegenerative Diseases and Geriatric Psychiatry, Medical Faculty, University Hospital Bonn, 53127 Bonn, Germany
- John W. M. Martens
- Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands
- Dieter Niederacher
- Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany
- Peter Nürnberg
- Center for Molecular Medicine Cologne (CMMC), Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
- Claus-Eric Ott
- Institute of Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, 13353 Berlin, Germany
- Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany
- Paul D. P. Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Alfredo Ramirez
- Division for Neurogenetics and Molecular Psychiatry, Medical Faculty, University of Cologne, 50937 Cologne, Germany
- Juliane Ramser
- Division of Gynaecology and Obstetrics, Klinikum Rechts der Isar der Technischen Universität München, 81675 Munich, Germany
- Steffi Riedel-Heller
- Institute of Social Medicine, Occupational Health and Public Health, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany
- Gunnar Schmidt
- Institute of Human Genetics, Hannover Medical School, 30625 Hannover, Germany
- Mitul Shah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK
- Martin Scherer
- Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Antje Stäbler
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany
- Tim M. Strom
- Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany
- Christian Sutter
- Institute of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany
- Holger Thiele
- Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
- Christi J. van Asperen
- Department of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, The Netherlands
- Lizet van der Kolk
- Family Cancer Clinic, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands
- Rob B. van der Luijt
- Department of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, The Netherlands
- Alexander E. Volk
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Michael Wagner
- Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, 53127 Bonn, Germany
- Quinten Waisfisz
- Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands
- Qin Wang
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Shan Wang-Gohrke
- Department of Gynaecology and Obstetrics, University of Ulm, 89081 Ulm, Germany
- Bernhard H. F. Weber
- Institute of Human Genetics, Regensburg University, 93053 Regensburg, Germany
- Genome of the Netherlands Project
- GHS Study Group
- Peter Devilee
- Department of Pathology, Department of Human Genetics, Leiden University Medical Center, 2333 Leiden, The Netherlands
- Sean Tavtigian
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
- Gary D. Bader
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada
- Alfons Meindl
- Division of Gynaecology and Obstetrics, Klinikum Rechts der Isar der Technischen Universität München, 81675 Munich, Germany
- David E. Goldgar
- Department of Dermatology, University of Utah, Salt Lake City, UT 84103, USA
- Irene L. Andrulis
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada
- Rita K. Schmutzler
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
- Douglas F. Easton
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Marjanka K. Schmidt
- Division of Molecular Pathology, The Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands
- Eric Hahnen
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
- Jacques Simard
- Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada
- DOI
- https://doi.org/10.3390/cancers14143363
- Journal volume & issue
-
Vol. 14,
no. 14
p. 3363
Abstract
Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
Keywords