Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer.

Autor: Weber-Lassalle N; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Borde J; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Weber-Lassalle K; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Horváth J; Institute for Human Genetics, University Hospital Muenster, Muenster, Germany., Niederacher D; Department of Gynaecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany., Arnold N; Institute of Clinical Molecular Biology, Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany., Kaulfuß S; Institute of Human Genetics, University Medical Center, Georg August University, Goettingen, Germany., Ernst C; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Paul VG; Institute for Human Genetics, University Hospital Muenster, Muenster, Germany., Honisch E; Department of Gynaecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany., Klaschik K; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Volk AE; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Kubisch C; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Rapp S; Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Lichey N; Institute for Human Genetics, University Hospital Muenster, Muenster, Germany., Altmüller J; Cologne Center for Genomics, University of Cologne, Cologne, Germany.; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Lepkes L; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Pohl-Rescigno E; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Thiele H; Cologne Center for Genomics, University of Cologne, Cologne, Germany., Nürnberg P; Cologne Center for Genomics, University of Cologne, Cologne, Germany.; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Larsen M; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Richters L; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Rhiem K; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Wappenschmidt B; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Engel C; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.; LIFE Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany., Meindl A; Department of Gynaecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany., Schmutzler RK; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany., Hahnen E; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany. eric.hahnen@uk-koeln.de., Hauke J; Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany.
Jazyk: angličtina
Zdroj: Breast cancer research : BCR [Breast Cancer Res] 2019 Apr 29; Vol. 21 (1), pp. 55. Date of Electronic Publication: 2019 Apr 29.
DOI: 10.1186/s13058-019-1137-9
Abstrakt: Background: The role of the BARD1 gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed to assess the role of deleterious BARD1 germline variants in BC/OC predisposition in a sample of 4920 BRCA1/2-negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC).
Methods: A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in BARD1. All patients met the inclusion criteria of the GC-HBOC for germline testing and reported at least one relative with BC or OC. Additional control datasets (Exome Aggregation Consortium, ExAC; Fabulous Ladies Over Seventy, FLOSSIES) were included for the calculation of odds ratios (ORs).
Results: We identified LoF variants in 23 of 4469 BC index patients (0.51%) and in 36 of 37,265 control individuals (0.10%), resulting in an OR of 5.35 (95% confidence interval [CI] = 3.17-9.04; P < 0.00001). BARD1-mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24-60 years) compared with the overall study sample (48.6 years, range 17-92 years; P = 0.00347). In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78-25.08; P < 0.00001) was observed. An OR of 7.43 (95% CI = 4.26-12.98; P < 0.00001) was observed when stratified for an AAD < 50 years. LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82-6.45; P = 0.11217). Overall, rare and predicted damaging BARD1 missense variants were significantly more prevalent in BC index patients compared with control individuals (OR = 2.15; 95% CI = 1.26-3.67; P = 0.00723). Neither LoF variants nor predicted damaging rare missense variants in BARD1 were identified in 451 familial index patients with OC.
Conclusions: Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants.
Databáze: MEDLINE
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