TY  - JOUR
A1  - Weber-Lassalle, Nana
A1  - Hauke, Jan
A1  - Ramser, Juliane
A1  - Richters, Lisa
A1  - Groß, Eva
A1  - Blümcke, Britta
A1  - Gehrig, Andrea
A1  - Kahlert, Anne-Karin
A1  - Müller, Clemens R.
A1  - Hackmann, Karl
A1  - Honisch, Ellen
A1  - Weber-Lassalle, Konstantin
A1  - Niederacher, Dieter
A1  - Borde, Julika
A1  - Thiele, Holger
A1  - Ernst, Corinna
A1  - Altmüller, Janine
A1  - Neidhardt, Guido
A1  - Nürnberg, Peter
A1  - Klaschik, Kristina
A1  - Schroeder, Christopher
A1  - Platzer, Konrad
A1  - Volk, Alexander E.
A1  - Wang-Gohrke, Shan
A1  - Just, Walter
A1  - Auber, Bernd
A1  - Kubisch, Christian
A1  - Schmidt, Gunnar
A1  - Horvath, Judit
A1  - Wappenschmidt, Barbara
A1  - Engel, Christoph
A1  - Arnold, Norbert
A1  - Dworniczak, Bernd
A1  - Rhiem, Kerstin
A1  - Meindl, Alfons
A1  - Schmutzler, Rita K.
A1  - Hahnen, Eric
T1  - BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer
JF  - Breast Cancer Research
N2  - Background
Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial.

Methods
To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants.

Results
BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99–59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00–3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70–2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43–9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients.

Conclusions
To avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded.
KW  - breast cancer
KW  - ovarian cancer
KW  - BRIP1 gene
KW  - germline mutations
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233433
VL  - 20
ER  - 
TY  - JOUR
A1  - Sepahi, Ilnaz
A1  - Faust, Ulrike
A1  - Sturm, Marc
A1  - Bosse, Kristin
A1  - Kehrer, Martin
A1  - Heinrich, Tilman
A1  - Grundman-Hauser, Kathrin
A1  - Bauer, Peter
A1  - Ossowski, Stephan
A1  - Susak, Hana
A1  - Varon, Raymonda
A1  - Schröck, Evelin
A1  - Niederacher, Dieter
A1  - Auber, Bernd
A1  - Sutter, Christian
A1  - Arnold, Norbert
A1  - Hahnen, Eric
A1  - Dworniczak, Bernd
A1  - Wang-Gorke, Shan
A1  - Gehrig, Andrea
A1  - Weber, Bernhard H. F.
A1  - Engel, Christoph
A1  - Lemke, Johannes R.
A1  - Hartkopf, Andreas
A1  - Huu Phuc, Nguyen
A1  - Riess, Olaf
A1  - Schroeder, Christopher
T1  - Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women
JF  - BMC Cancer
N2  - Background
Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon.

Methods
We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways.

Results
Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00–27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05.

Conclusions
To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results.
KW  - breast cancer
KW  - age at onset
KW  - DNA-repair genes
KW  - next-generation-sequencing
KW  - panel sequencing
KW  - extreme phenotypes
KW  - hereditary breast and ovarian cancer
KW  - BRCA1
KW  - DNA-repair
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237676
VL  - 19
ER  - 
TY  - JOUR
A1  - Rolfes, Muriel
A1  - Borde, Julika
A1  - Möllenhoff, Kathrin
A1  - Kayali, Mohamad
A1  - Ernst, Corinna
A1  - Gehrig, Andrea
A1  - Sutter, Christian
A1  - Ramser, Juliane
A1  - Niederacher, Dieter
A1  - Horváth, Judit
A1  - Arnold, Norbert
A1  - Meindl, Alfons
A1  - Auber, Bernd
A1  - Rump, Andreas
A1  - Wang-Gohrke, Shan
A1  - Ritter, Julia
A1  - Hentschel, Julia
A1  - Thiele, Holger
A1  - Altmüller, Janine
A1  - Nürnberg, Peter
A1  - Rhiem, Kerstin
A1  - Engel, Christoph
A1  - Wappenschmidt, Barbara
A1  - Schmutzler, Rita K.
A1  - Hahnen, Eric
A1  - Hauke, Jan
T1  - Prevalence of cancer predisposition germline variants in male breast cancer patients: results of the German Consortium for Hereditary Breast and Ovarian Cancer
JF  - Cancers
N2  - Male breast cancer (mBC) is associated with a high prevalence of pathogenic variants (PVs) in the BRCA2 gene; however, data regarding other BC predisposition genes are limited. In this retrospective multicenter study, we investigated the prevalence of PVs in BRCA1/2 and 23 non-BRCA1/2 genes using a sample of 614 patients with mBC, recruited through the centers of the German Consortium for Hereditary Breast and Ovarian Cancer. A high proportion of patients with mBC carried PVs in BRCA2 (23.0%, 142/614) and BRCA1 (4.6%, 28/614). The prevalence of BRCA1/2 PVs was 11.0% in patients with mBC without a family history of breast and/or ovarian cancer. Patients with BRCA1/2 PVs did not show an earlier disease onset than those without. The predominant clinical presentation of tumor phenotypes was estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and HER2-negative (77.7%); further, 10.2% of the tumors were triple-positive, and 1.2% were triple-negative. No association was found between ER/PR/HER2 status and BRCA1/2 PV occurrence. Comparing the prevalence of protein-truncating variants (PTVs) between patients with mBC and control data (ExAC, n = 27,173) revealed significant associations of PTVs in both BRCA1 and BRCA2 with mBC (BRCA1: OR = 17.04, 95% CI = 10.54–26.82, p < 10\(^{−5}\); BRCA2: OR = 77.71, 95% CI = 58.71–102.33, p < 10\(^{−5}\)). A case-control investigation of 23 non-BRCA1/2 genes in 340 BRCA1/2-negative patients and ExAC controls revealed significant associations of PTVs in CHEK2, PALB2, and ATM with mBC (CHEK2: OR = 3.78, 95% CI = 1.59–7.71, p = 0.002; PALB2: OR = 14.77, 95% CI = 5.02–36.02, p < 10\(^{−5}\); ATM: OR = 3.36, 95% CI = 0.89–8.96, p = 0.04). Overall, our findings support the benefit of multi-gene panel testing in patients with mBC irrespective of their family history, age at disease onset, and tumor phenotype.
KW  - breast neoplasms
KW  - male breast cancer
KW  - breast cancer predisposition genes
KW  - genetic testing
KW  - familial breast cancer
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281758
SN  - 2072-6694
VL  - 14
IS  - 13
ER  -