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 Dumont¹, Nana Weber-Lassalle², Charles Joly-Beauparlant¹, Corinna Ernst², Arnaud Droit¹, Bing-Jian Feng^{3

4}, Stéphane Dubois¹, Annie-Claude Collin-Deschesnes¹, Penny Soucy¹, Maxime Vallée¹, Frédéric Fournier¹, Audrey Lemaçon¹, Muriel A Adank⁵, Jamie Allen⁶, Janine Altmüller⁷, Norbert Arnold⁸, Margreet G E M Ausems⁹, Riccardo Berutti¹⁰, Manjeet K Bolla⁶, Shelley Bull^{11

12}, Sara Carvalho⁶, Sten Cornelissen¹³, Michael R Dufault¹⁴, Alison M Dunning¹⁵, Christoph Engel¹⁶, Andrea Gehrig¹⁷, Willemina R R Geurts-Giele¹⁸, Christian Gieger^{19

20}, Jessica Green^{11

21}, Karl Hackmann²², Mohamed Helmy^{23

24

25}, Julia Hentschel²⁶, Frans B L Hogervorst⁵, Antoinette Hollestelle²⁷, Maartje J Hooning²⁷, Judit Horváth²⁸, M Arfan Ikram²⁹, Silke Kaulfuß³⁰, Renske Keeman¹³, Da Kuang^{21

23}, Craig Luccarini¹⁵, Wolfgang Maier³¹, John W M Martens²⁷, Dieter Niederacher³², Peter Nürnberg³³, Claus-Eric Ott³⁴, Annette Peters^{19

35}, Paul D P Pharoah^{6

15}, Alfredo Ramirez³⁶, Juliane Ramser³⁷, Steffi Riedel-Heller³⁸, Gunnar Schmidt³⁹, Mitul Shah¹⁵, Martin Scherer⁴⁰, Antje Stäbler⁴¹, Tim M Strom¹⁰, Christian Sutter⁴², Holger Thiele⁷, Christi J van Asperen⁴³, Lizet van der Kolk⁵, Rob B van der Luijt^{43

44}, Alexander E Volk⁴⁵, Michael Wagner⁴⁶, Quinten Waisfisz⁴⁷, Qin Wang⁶, Shan Wang-Gohrke⁴⁸, Bernhard H F Weber^{49

50}, Genome Of The Netherlands Project, Ghs Study Group, Peter Devilee⁵¹, Sean Tavtigian^{4

52}, Gary D Bader^{11

21

23

53

54}, Alfons Meindl³⁷, David E Goldgar^{3

4}, Irene L Andrulis^{11

21}, Rita K Schmutzler², Douglas F Easton^{6

15}, Marjanka K Schmidt^{13

55}, Eric Hahnen², Jacques Simard^{1

56}

Affiliations

¹ Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada.
² 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.
³ Department of Dermatology, University of Utah, Salt Lake City, UT 84103, USA.
⁴ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
⁵ Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands.
⁶ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
⁷ Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
⁸ Institute of Clinical Molecular Biology, Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, 24105 Kiel, Germany.
⁹ Division Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Center Utrecht, 3584 Utrecht, The Netherlands.
¹⁰ Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
¹¹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada.
¹² Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
¹³ Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands.
¹⁴ Precision Medicine and Computational Biology, Sanofi Genzyme, Cambridge, MA 02142, USA.
¹⁵ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
¹⁶ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany.
¹⁷ Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University of Würzburg, 97074 Würzburg, Germany.
¹⁸ Department of Clinical Genetics, Erasmus University Medical Center, 3015 Rotterdam, The Netherlands.
¹⁹ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
²⁰ Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, 85764 Neuherberg, Germany.
²¹ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
²² Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
²³ The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
²⁴ Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore 138632, Singapore.
²⁵ Department of Computer Science, Lakehead University, Thunder Bay, ON P7B 5E1, Canada.
²⁶ Institute of Human Genetics, University Leipzig, 04103 Leipzig, Germany.
²⁷ Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands.
²⁸ Institute of Human Genetics, University of Münster, 48149 Münster, Germany.
²⁹ Department of Epidemiology, Erasmus MC University Medical Center, 3015 Rotterdam, The Netherlands.
³⁰ Institute of Human Genetics, University Medical Center Göttingen, 37075 Göttingen, Germany.
³¹ German Center for Neurodegenerative Diseases (DZNE), Department of Neurodegenerative Diseases and Geriatric Psychiatry, Medical Faculty, University Hospital Bonn, 53127 Bonn, Germany.
³² Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
³³ Center for Molecular Medicine Cologne (CMMC), Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
³⁴ 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.
³⁵ Department of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig-Maximilians-Universität München, 80539 Munich, Germany.
³⁶ Division for Neurogenetics and Molecular Psychiatry, Medical Faculty, University of Cologne, 50937 Cologne, Germany.
³⁷ Division of Gynaecology and Obstetrics, Klinikum Rechts der Isar der Technischen Universität München, 81675 Munich, Germany.
³⁸ Institute of Social Medicine, Occupational Health and Public Health, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany.
³⁹ Institute of Human Genetics, Hannover Medical School, 30625 Hannover, Germany.
⁴⁰ Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁴¹ Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
⁴² Institute of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
⁴³ Department of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, The Netherlands.
⁴⁴ Department of Medical Genetics, University Medical Center, 3584 Utrecht, The Netherlands.
⁴⁵ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁴⁶ Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, 53127 Bonn, Germany.
⁴⁷ Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands.
⁴⁸ Department of Gynaecology and Obstetrics, University of Ulm, 89081 Ulm, Germany.
⁴⁹ Institute of Human Genetics, Regensburg University, 93053 Regensburg, Germany.
⁵⁰ Institute of Clinical Human Genetics, University Hospital Regensburg, 93053 Regensburg, Germany.
⁵¹ Department of Pathology, Department of Human Genetics, Leiden University Medical Center, 2333 Leiden, The Netherlands.
⁵² Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
⁵³ Department of Computer Science, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁵⁴ Princess Margaret Research Institute, University Health Network, Toronto, ON M5G 0A3, Canada.
⁵⁵ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands.
⁵⁶ Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec, QC G1V 0A6, Canada.

PMID: 35884425
PMCID: PMC9317824
DOI: 10.3390/cancers14143363

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 et al. Cancers (Basel). 2022.

. 2022 Jul 11;14(14):3363.

doi: 10.3390/cancers14143363.

Authors

Affiliations

¹ Genomics Center, CHU de Québec-Université Laval Research Center, 2705 Laurier Boulevard, Quebec City, QC GIV 4G2, Canada.
² 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.
³ Department of Dermatology, University of Utah, Salt Lake City, UT 84103, USA.
⁴ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
⁵ Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands.
⁶ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
⁷ Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
⁸ Institute of Clinical Molecular Biology, Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, 24105 Kiel, Germany.
⁹ Division Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Center Utrecht, 3584 Utrecht, The Netherlands.
¹⁰ Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
¹¹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada.
¹² Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
¹³ Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands.
¹⁴ Precision Medicine and Computational Biology, Sanofi Genzyme, Cambridge, MA 02142, USA.
¹⁵ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
¹⁶ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany.
¹⁷ Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University of Würzburg, 97074 Würzburg, Germany.
¹⁸ Department of Clinical Genetics, Erasmus University Medical Center, 3015 Rotterdam, The Netherlands.
¹⁹ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
²⁰ Research Unit Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, 85764 Neuherberg, Germany.
²¹ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
²² Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
²³ The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
²⁴ Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore 138632, Singapore.
²⁵ Department of Computer Science, Lakehead University, Thunder Bay, ON P7B 5E1, Canada.
²⁶ Institute of Human Genetics, University Leipzig, 04103 Leipzig, Germany.
²⁷ Department of Medical Oncology, Erasmus MC Cancer Institute, 3015 Rotterdam, The Netherlands.
²⁸ Institute of Human Genetics, University of Münster, 48149 Münster, Germany.
²⁹ Department of Epidemiology, Erasmus MC University Medical Center, 3015 Rotterdam, The Netherlands.
³⁰ Institute of Human Genetics, University Medical Center Göttingen, 37075 Göttingen, Germany.
³¹ German Center for Neurodegenerative Diseases (DZNE), Department of Neurodegenerative Diseases and Geriatric Psychiatry, Medical Faculty, University Hospital Bonn, 53127 Bonn, Germany.
³² Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
³³ Center for Molecular Medicine Cologne (CMMC), Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
³⁴ 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.
³⁵ Department of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig-Maximilians-Universität München, 80539 Munich, Germany.
³⁶ Division for Neurogenetics and Molecular Psychiatry, Medical Faculty, University of Cologne, 50937 Cologne, Germany.
³⁷ Division of Gynaecology and Obstetrics, Klinikum Rechts der Isar der Technischen Universität München, 81675 Munich, Germany.
³⁸ Institute of Social Medicine, Occupational Health and Public Health, Faculty of Medicine, University of Leipzig, 04103 Leipzig, Germany.
³⁹ Institute of Human Genetics, Hannover Medical School, 30625 Hannover, Germany.
⁴⁰ Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁴¹ Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
⁴² Institute of Human Genetics, University Hospital Heidelberg, 69120 Heidelberg, Germany.
⁴³ Department of Clinical Genetics, Leiden University Medical Center, 2333 Leiden, The Netherlands.
⁴⁴ Department of Medical Genetics, University Medical Center, 3584 Utrecht, The Netherlands.
⁴⁵ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
⁴⁶ Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, 53127 Bonn, Germany.
⁴⁷ Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 Amsterdam, The Netherlands.
⁴⁸ Department of Gynaecology and Obstetrics, University of Ulm, 89081 Ulm, Germany.
⁴⁹ Institute of Human Genetics, Regensburg University, 93053 Regensburg, Germany.
⁵⁰ Institute of Clinical Human Genetics, University Hospital Regensburg, 93053 Regensburg, Germany.
⁵¹ Department of Pathology, Department of Human Genetics, Leiden University Medical Center, 2333 Leiden, The Netherlands.
⁵² Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
⁵³ Department of Computer Science, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁵⁴ Princess Margaret Research Institute, University Health Network, Toronto, ON M5G 0A3, Canada.
⁵⁵ Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, 1066 Amsterdam, The Netherlands.
⁵⁶ Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec, QC G1V 0A6, Canada.

PMID: 35884425
PMCID: PMC9317824
DOI: 10.3390/cancers14143363

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 < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to 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: breast cancer; genetic susceptibility; moderate-penetrance genes; whole-exome sequencing.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Figures

**Figure 1**
Study design for breast cancer susceptibility gene discovery by whole-exome sequencing (A) and validation by targeted enrichment sequencing (B).

**Figure 2**
Risk of breast cancer overall and tumor subtypes associated with loss-of-function and missense variants in known or suspected breast cancer susceptibility genes included in breast cancer gene panels. Shown are odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer overall, estrogen receptor (ER)-negative breast cancer, and ER-positive breast cancer associated with loss-of-function variants (A) and missense variants (B) in genes for which evidence of association was observed in at least one of the analyses. Red circles indicate p-value < 0.05. * no loss-of-function variants were observed in *MEN1*.

**Figure 3**
Risk of breast cancer overall and tumor subtypes associated with loss-of-function and missense variants in a subset of targeted genes identified at the discovery stage. Shown are odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer overall, estrogen receptor (ER)-negative breast cancer, and ER-positive breast cancer associated with loss-of-function variants (A), missense variants (B), and combined loss-of-function and missense variants (C) in genes for which evidence of association was observed in at least one of the analyses. Red circles indicate p-value < 0.05. * no loss-of-function variants were observed in *SIPA1L1* and *NTRK3*.

See this image and copyright information in PMC

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Grants and funding

GPH-129344/the Government of Canada through Genome Canada and the Canadian Institutes of Health Re-search (GPH-129344), the Ministère de l'Économie, de la Science et de l'Innovation du Québec through Genome Quebec, and the Quebec Breast Cancer Foundation

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

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