Cancer Medicine (Apr 2018)
Gene panel testing of 5589 BRCA1/2‐negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer
- Jan Hauke,
- Judit Horvath,
- Eva Groß,
- Andrea Gehrig,
- Ellen Honisch,
- Karl Hackmann,
- Gunnar Schmidt,
- Norbert Arnold,
- Ulrike Faust,
- Christian Sutter,
- Julia Hentschel,
- Shan Wang‐Gohrke,
- Mateja Smogavec,
- Bernhard H. F. Weber,
- Nana Weber‐Lassalle,
- Konstantin Weber‐Lassalle,
- Julika Borde,
- Corinna Ernst,
- Janine Altmüller,
- Alexander E. Volk,
- Holger Thiele,
- Verena Hübbel,
- Peter Nürnberg,
- Katharina Keupp,
- Beatrix Versmold,
- Esther Pohl,
- Christian Kubisch,
- Sabine Grill,
- Victoria Paul,
- Natalie Herold,
- Nadine Lichey,
- Kerstin Rhiem,
- Nina Ditsch,
- Christian Ruckert,
- Barbara Wappenschmidt,
- Bernd Auber,
- Andreas Rump,
- Dieter Niederacher,
- Thomas Haaf,
- Juliane Ramser,
- Bernd Dworniczak,
- Christoph Engel,
- Alfons Meindl,
- Rita K. Schmutzler,
- Eric Hahnen
Affiliations
- Jan Hauke
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Judit Horvath
- Institute for Human Genetics University Hospital Muenster Muenster Germany
- Eva Groß
- Department of Gynaecology and Obstetrics Division of Tumor Genetics Klinikum rechts der Isar Technical University Munich Munich Germany
- Andrea Gehrig
- Institute of Human Genetics Julius‐Maximilians‐Universität Würzburg Würzburg Germany
- Ellen Honisch
- Department of Gynaecology and Obstetrics University Hospital Duesseldorf Heinrich‐Heine University Duesseldorf Duesseldorf Germany
- Karl Hackmann
- Institute for Clinical Genetics Technische Universitaet Dresden Dresden Germany
- Gunnar Schmidt
- Department of Human Genetics Hannover Medical School Hannover Germany
- Norbert Arnold
- Department of Gynaecology and Obstetrics Institute of Clinical Molecular Biology University Hospital of Schleswig‐Holstein, Campus Kiel Christian‐Albrechts University Kiel Kiel Germany
- Ulrike Faust
- Institute of Medical Genetics and Applied Genomics University Hospital Tuebingen Tuebingen Germany
- Christian Sutter
- Institute of Human Genetics University of Heidelberg Heidelberg Germany
- Julia Hentschel
- Institute of Human Genetics University of Leipzig Hospitals and Clinics Leipzig Germany
- Shan Wang‐Gohrke
- Department of Gynaecology and Obstetrics University Hospital Ulm Ulm Germany
- Mateja Smogavec
- Institute of Human Genetics University Medical Center Georg August University Goettingen Germany
- Bernhard H. F. Weber
- Institute of Human Genetics University of Regensburg Regensburg Germany
- Nana Weber‐Lassalle
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Konstantin Weber‐Lassalle
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Julika Borde
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Corinna Ernst
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Janine Altmüller
- Cologne Center for Genomics University of Cologne Cologne Germany
- Alexander E. Volk
- Institute of Human Genetics University Medical Center Hamburg‐Eppendorf Hamburg Germany
- Holger Thiele
- Cologne Center for Genomics University of Cologne Cologne Germany
- Verena Hübbel
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Peter Nürnberg
- Cologne Center for Genomics University of Cologne Cologne Germany
- Katharina Keupp
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Beatrix Versmold
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Esther Pohl
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Christian Kubisch
- Institute of Human Genetics University Medical Center Hamburg‐Eppendorf Hamburg Germany
- Sabine Grill
- Department of Gynaecology and Obstetrics Division of Tumor Genetics Klinikum rechts der Isar Technical University Munich Munich Germany
- Victoria Paul
- Institute for Human Genetics University Hospital Muenster Muenster Germany
- Natalie Herold
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Nadine Lichey
- Institute for Human Genetics University Hospital Muenster Muenster Germany
- Kerstin Rhiem
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Nina Ditsch
- Department of Obstetrics and Gynaecology Ludwig‐Maximilians‐University of Munich Munich Germany
- Christian Ruckert
- Institute for Human Genetics University Hospital Muenster Muenster Germany
- Barbara Wappenschmidt
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Bernd Auber
- Department of Human Genetics Hannover Medical School Hannover Germany
- Andreas Rump
- Institute for Clinical Genetics Technische Universitaet Dresden Dresden Germany
- Dieter Niederacher
- Department of Gynaecology and Obstetrics University Hospital Duesseldorf Heinrich‐Heine University Duesseldorf Duesseldorf Germany
- Thomas Haaf
- Institute of Human Genetics Julius‐Maximilians‐Universität Würzburg Würzburg Germany
- Juliane Ramser
- Department of Gynaecology and Obstetrics Division of Tumor Genetics Klinikum rechts der Isar Technical University Munich Munich Germany
- Bernd Dworniczak
- Institute for Human Genetics University Hospital Muenster Muenster Germany
- Christoph Engel
- Institute for Medical Informatics, Statistics and Epidemiology University of Leipzig Leipzig Germany
- Alfons Meindl
- Department of Gynaecology and Obstetrics Division of Tumor Genetics Klinikum rechts der Isar Technical University Munich Munich Germany
- Rita K. Schmutzler
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- Eric Hahnen
- Center for Hereditary Breast and Ovarian Cancer Center for Integrated Oncology (CIO) Medical Faculty University Hospital Cologne Cologne Germany
- DOI
- https://doi.org/10.1002/cam4.1376
- Journal volume & issue
-
Vol. 7,
no. 4
pp. 1349 – 1358
Abstract
Abstract The prevalence of germ line mutations in non‐BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple‐negative breast cancer (TNBC) and estrogen receptor (ER)‐negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)‐positive tumors.
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