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. 2019 Apr 29;21(1):55.
doi: 10.1186/s13058-019-1137-9.

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

Nana Weber-Lassalle  1 , Julika Borde  1 , Konstantin Weber-Lassalle  1 , Judit Horváth  2 , Dieter Niederacher  3 , Norbert Arnold  4 , Silke Kaulfuß  5 , Corinna Ernst  1 , Victoria G Paul  2 , Ellen Honisch  3 , Kristina Klaschik  1 , Alexander E Volk  6 , Christian Kubisch  6 , Steffen Rapp  7 , Nadine Lichey  2 , Janine Altmüller  8   9 , Louisa Lepkes  1 , Esther Pohl-Rescigno  1 , Holger Thiele  8 , Peter Nürnberg  8   9 , Mirjam Larsen  1 , Lisa Richters  1 , Kerstin Rhiem  1 , Barbara Wappenschmidt  1 , Christoph Engel  10   11 , Alfons Meindl  12 , Rita K Schmutzler  1 , Eric Hahnen  13 , Jan Hauke  1
Affiliations

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

Nana Weber-Lassalle et al. Breast Cancer Res. .

Abstract

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.

Keywords: BARD1; Early onset breast cancer; Germline mutations; Ovarian cancer.

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Conflict of interest statement

Ethics approval and consent to participate

Written informed consent was obtained from all patients and control individuals, and ethical approval was granted by the Ethics Committee of the University of Cologne (07-048).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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