Universität zu Köln

Weber-Lassalle, Nana, Borde, Julika, Weber-Lassalle, Konstantin, Horvath, Judit, Niederacher, Dieter, Arnold, Norbert ORCID: 0000-0003-4523-8808, Kaulfuss, Silke, Ernst, Corinna, Paul, Victoria G., Honisch, Ellen, Klaschik, Kristina, Volk, Alexander E., Kubisch, Christian, Rapp, Steffen, Lichey, Nadine, Altmueller, Janine, Lepkes, Louisa, Pohl-Rescigno, Esther, Thiele, Holger, Nuernberg, Peter, Larsen, Mirjam, Richters, Lisa, Rhiem, Kerstin, Wappenschmidt, Barbara, Engel, Christoph ORCID: 0000-0002-7247-282X, Meindl, Alfons, Schmutzler, Rita K., Hahnen, Eric and Hauke, Jan (2019). Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer. Breast Cancer Res., 21. LONDON: BMC. ISSN 1465-542X

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Abstract

BackgroundThe 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).MethodsA 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).ResultsWe identified LoF variants in 23 of 4469BC 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; 42.3years, range 24-60years) compared with the overall study sample (48.6years, range 17-92years; P=0.00347). In the subgroup of BC index patients with an AAD <40years, 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 <50years. LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD 50years (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.ConclusionsDue 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Weber-Lassalle, Nana UNSPECIFIED UNSPECIFIED UNSPECIFIED Borde, Julika UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber-Lassalle, Konstantin UNSPECIFIED UNSPECIFIED UNSPECIFIED Horvath, Judit UNSPECIFIED UNSPECIFIED UNSPECIFIED Niederacher, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Arnold, Norbert UNSPECIFIED orcid.org/0000-0003-4523-8808 UNSPECIFIED Kaulfuss, Silke UNSPECIFIED UNSPECIFIED UNSPECIFIED Ernst, Corinna UNSPECIFIED UNSPECIFIED UNSPECIFIED Paul, Victoria G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Honisch, Ellen UNSPECIFIED UNSPECIFIED UNSPECIFIED Klaschik, Kristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Volk, Alexander E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubisch, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Rapp, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Lichey, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Lepkes, Louisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Pohl-Rescigno, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Larsen, Mirjam UNSPECIFIED UNSPECIFIED UNSPECIFIED Richters, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Rhiem, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Wappenschmidt, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Engel, Christoph UNSPECIFIED orcid.org/0000-0002-7247-282X UNSPECIFIED Meindl, Alfons UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmutzler, Rita K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hahnen, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED Hauke, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-150303
DOI:	10.1186/s13058-019-1137-9
Journal or Publication Title:	Breast Cancer Res.
Volume:	21
Date:	2019
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1465-542X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MUTATIONS; BRCA1; PROTEIN Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15030