Germline loss-of-function variants in the BARD1 gene are associated with familial breast cancer

N Weber-Lassalle; J Borde; K Weber-Lassalle; K Klaschik; G Neidhardt; C Ernst; B Blümcke; K Klonowska; A Volk; C Kubisch; R Baber; C Engel; P Kozlowski; E Hahnen; R Schmutzler; J Hauke

doi:10.1055/s-0038-1651818

Senologie - Zeitschrift für Mammadiagnostik und -therapie, Table of Contents

Senologie - Zeitschrift für Mammadiagnostik und -therapie 2018; 15(02): e51
DOI: 10.1055/s-0038-1651818

Abstracts

Georg Thieme Verlag KG Stuttgart · New York

Germline loss-of-function variants in the BARD1 gene are associated with familial breast cancer

N Weber-Lassalle

¹Uniklinik Köln, Zentrum Familiärer Brust-und Eierstockkrebs, Köln, Deutschland

²Uniklinik Köln, Center for Integrated Oncology (CIO), Köln, Deutschland

,

J Borde

¹Uniklinik Köln, Zentrum Familiärer Brust-und Eierstockkrebs, Köln, Deutschland

²Uniklinik Köln, Center for Integrated Oncology (CIO), Köln, Deutschland

,

K Weber-Lassalle

¹Uniklinik Köln, Zentrum Familiärer Brust-und Eierstockkrebs, Köln, Deutschland

²Uniklinik Köln, Center for Integrated Oncology (CIO), Köln, Deutschland

,

K Klaschik

¹Uniklinik Köln, Zentrum Familiärer Brust-und Eierstockkrebs, Köln, Deutschland

²Uniklinik Köln, Center for Integrated Oncology (CIO), Köln, Deutschland

,

G Neidhardt

¹Uniklinik Köln, Zentrum Familiärer Brust-und Eierstockkrebs, Köln, Deutschland

²Uniklinik Köln, Center for Integrated Oncology (CIO), Köln, Deutschland

,

C Ernst

¹Uniklinik Köln, Zentrum Familiärer Brust-und Eierstockkrebs, Köln, Deutschland

²Uniklinik Köln, Center for Integrated Oncology (CIO), Köln, Deutschland

,

B Blümcke

¹Uniklinik Köln, Zentrum Familiärer Brust-und Eierstockkrebs, Köln, Deutschland

²Uniklinik Köln, Center for Integrated Oncology (CIO), Köln, Deutschland

,

K Klonowska

³Institute of Bioorganic Chemistry, Department of Molecular Genetics, Poznan, Polen

,

A Volk

⁴Medical Center Hamburg-Eppendorf, Institute of Human Genetics, Hamburg, Deutschland

,

C Kubisch

⁴Medical Center Hamburg-Eppendorf, Institute of Human Genetics, Hamburg, Deutschland

,

R Baber

⁵Universiät Leipzig, LIFE-Leipzig Research Center for Civilization Diseases, Leipzig, Deutschland

⁶Universiät Leipzig, Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (ILM), Leipzig, Deutschland

,

C Engel

⁵Universiät Leipzig, LIFE-Leipzig Research Center for Civilization Diseases, Leipzig, Deutschland

⁷Universiät Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Deutschland

,

P Kozlowski

³Institute of Bioorganic Chemistry, Department of Molecular Genetics, Poznan, Polen

,

E Hahnen

¹Uniklinik Köln, Zentrum Familiärer Brust-und Eierstockkrebs, Köln, Deutschland

²Uniklinik Köln, Center for Integrated Oncology (CIO), Köln, Deutschland

,

R Schmutzler

¹Uniklinik Köln, Zentrum Familiärer Brust-und Eierstockkrebs, Köln, Deutschland

²Uniklinik Köln, Center for Integrated Oncology (CIO), Köln, Deutschland

,

J Hauke

¹Uniklinik Köln, Zentrum Familiärer Brust-und Eierstockkrebs, Köln, Deutschland

²Uniklinik Köln, Center for Integrated Oncology (CIO), Köln, Deutschland

› Author Affiliations

Abstract

Full Text

Introduction:

Recent studies revealed a weak association of BARD1 germline loss-of-function (LoF) variants with breast cancer (BC). We determined the BARD1 mutation prevalence in n = 3,348 well-characterized BC index patients of the German descent and geographically-matched female control individuals (GMCs; n = 2,196).

Methods:

Female BC index patients and GMCs were screened for LoF variants in the BARD1 gene by next generation sequencing. All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing. The SOPHiA DDM® platform (SOPHiA GENETICS®) was applied for the detection of copy number variations (CNVs) in a subset of 2,810 BC patients.

Results:

We identified 14 LoF variants (excluding CNVs) in 3,348 female BC index patients (carrier frequency [CF]: 0.42%) compared with 36 in a total of 36,694 controls (CF: 0.10%, OR = 4.276, 95%CI = 2.30 – 7.94, p = 0.00004). The CF in each control dataset was 0.07% (GMCs; n = 2,196), 0.11% (FLOSSIES; n = 7,325) and 0.10% (ExAC; n = 27,173), respectively. The BARD1 p.Gln564* variant was found in 6/14 patients. CNVs affecting the BARD1 gene were identified in 3/2,810 BC index patients (CNV CF = 0.11%), which is higher than that observed in the FLOSSIES database (2/7,325; CF = 0.03%). For the 17 BARD1 mutation carriers, the mean age of first BC diagnosis was 46 years (range 24 – 60) compared with 47 years (range 17 – 92) in the overall sample (n = 3,348).

Conclusion:

We observed a significant association of deleterious BARD1 variants with the BC phenotype and confirm BARD1 as a moderately-penetrant risk gene. The inclusion of CNVs is crucial for a comprehensive genetic screening of BC patients.