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 Hauke¹, Judit Horvath², Eva Groß³, Andrea Gehrig⁴, Ellen Honisch⁵, Karl Hackmann⁶, Gunnar Schmidt⁷, Norbert Arnold⁸, Ulrike Faust⁹, Christian Sutter¹⁰, Julia Hentschel¹¹, Shan Wang-Gohrke¹², Mateja Smogavec¹³, Bernhard H F Weber¹⁴, Nana Weber-Lassalle¹, Konstantin Weber-Lassalle¹, Julika Borde¹, Corinna Ernst¹, Janine Altmüller^{15

16

17}, Alexander E Volk¹⁸, Holger Thiele^{15

16

17}, Verena Hübbel¹, Peter Nürnberg^{15

16

17}, Katharina Keupp¹, Beatrix Versmold¹, Esther Pohl¹, Christian Kubisch¹⁸, Sabine Grill³, Victoria Paul², Natalie Herold¹, Nadine Lichey², Kerstin Rhiem¹, Nina Ditsch¹⁹, Christian Ruckert², Barbara Wappenschmidt¹, Bernd Auber⁷, Andreas Rump⁶, Dieter Niederacher⁵, Thomas Haaf⁴, Juliane Ramser³, Bernd Dworniczak², Christoph Engel^{20

21}, Alfons Meindl³, Rita K Schmutzler¹, Eric Hahnen¹

Affiliations

¹ Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
² Institute for Human Genetics, University Hospital Muenster, Muenster, Germany.
³ Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
⁴ Institute of Human Genetics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
⁵ Department of Gynaecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.
⁶ Institute for Clinical Genetics, Technische Universitaet Dresden, Dresden, Germany.
⁷ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
⁸ Department of Gynaecology and Obstetrics, Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
⁹ Institute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tuebingen, Germany.
¹⁰ Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
¹¹ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
¹² Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
¹³ Institute of Human Genetics, University Medical Center, Georg August University, Goettingen, Germany.
¹⁴ Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
¹⁵ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
¹⁶ Institute of Human Genetics, University of Cologne, Cologne, Germany.
¹⁷ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
¹⁸ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁹ Department of Obstetrics and Gynaecology, Ludwig-Maximilians-University of Munich, Munich, Germany.
²⁰ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
²¹ LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.

PMID: 29522266
PMCID: PMC5911592
DOI: 10.1002/cam4.1376

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 et al. Cancer Med. 2018 Apr.

. 2018 Apr;7(4):1349-1358.

doi: 10.1002/cam4.1376. Epub 2018 Mar 9.

Authors

Affiliations

¹ Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
² Institute for Human Genetics, University Hospital Muenster, Muenster, Germany.
³ Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
⁴ Institute of Human Genetics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
⁵ Department of Gynaecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.
⁶ Institute for Clinical Genetics, Technische Universitaet Dresden, Dresden, Germany.
⁷ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
⁸ Department of Gynaecology and Obstetrics, Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
⁹ Institute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tuebingen, Germany.
¹⁰ Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
¹¹ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
¹² Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
¹³ Institute of Human Genetics, University Medical Center, Georg August University, Goettingen, Germany.
¹⁴ Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
¹⁵ Cologne Center for Genomics, University of Cologne, Cologne, Germany.
¹⁶ Institute of Human Genetics, University of Cologne, Cologne, Germany.
¹⁷ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
¹⁸ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁹ Department of Obstetrics and Gynaecology, Ludwig-Maximilians-University of Munich, Munich, Germany.
²⁰ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
²¹ LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.

PMID: 29522266
PMCID: PMC5911592
DOI: 10.1002/cam4.1376

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.

Keywords: Breast cancer predisposition; hereditary breast cancer.

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References

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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

Affiliations

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

Authors

Affiliations

Abstract

References

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous