@article{SepahiFaustSturmetal.2019,
  author    = {Sepahi, Ilnaz and Faust, Ulrike and Sturm, Marc and Bosse, Kristin and Kehrer, Martin and Heinrich, Tilman and Grundman-Hauser, Kathrin and Bauer, Peter and Ossowski, Stephan and Susak, Hana and Varon, Raymonda and Schr{\"o}ck, Evelin and Niederacher, Dieter and Auber, Bernd and Sutter, Christian and Arnold, Norbert and Hahnen, Eric and Dworniczak, Bernd and Wang-Gorke, Shan and Gehrig, Andrea and Weber, Bernhard H. F. and Engel, Christoph and Lemke, Johannes R. and Hartkopf, Andreas and Huu Phuc, Nguyen and Riess, Olaf and Schroeder, Christopher},
  title     = {Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women},
  series = {BMC Cancer},
  volume    = {19},
  journal   = {BMC Cancer},
  doi       = {10.1186/s12885-019-5946-0},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237676},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}
@article{WeberLassalleHaukeRamseretal.2018,
  author    = {Weber-Lassalle, Nana and Hauke, Jan and Ramser, Juliane and Richters, Lisa and Groß, Eva and Bl{\"u}mcke, Britta and Gehrig, Andrea and Kahlert, Anne-Karin and M{\"u}ller, Clemens R. and Hackmann, Karl and Honisch, Ellen and Weber-Lassalle, Konstantin and Niederacher, Dieter and Borde, Julika and Thiele, Holger and Ernst, Corinna and Altm{\"u}ller, Janine and Neidhardt, Guido and N{\"u}rnberg, Peter and Klaschik, Kristina and Schroeder, Christopher and Platzer, Konrad and Volk, Alexander E. and Wang-Gohrke, Shan and Just, Walter and Auber, Bernd and Kubisch, Christian and Schmidt, Gunnar and Horvath, Judit and Wappenschmidt, Barbara and Engel, Christoph and Arnold, Norbert and Dworniczak, Bernd and Rhiem, Kerstin and Meindl, Alfons and Schmutzler, Rita K. and Hahnen, Eric},
  title     = {BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer},
  series = {Breast Cancer Research},
  volume    = {20},
  journal   = {Breast Cancer Research},
  doi       = {10.1186/s13058-018-0935-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233433},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}