@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{HaukeHorvathGrossetal.2018,
  author    = {Hauke, Jan and Horvath, Judit and Groß, Eva and Gehrig, Andrea and Honisch, Ellen and Hackmann, Karl and Schmidt, Gunnar and Arnold, Norbert and Faust, Ulrike and Sutter, Christian and Hentschel, Julia and Wang-Gohrke, Shan and Smogavec, Mateja and Weber, Bernhard H. F. and Weber-Lassalle, Nana and Weber-Lassalle, Konstantin and Borde, Julika and Ernst, Corinna and Altm{\"u}ller, Janine and Volk, Alexander E. and Thiele, Holger and H{\"u}bbel, Verena and N{\"u}rnberg, Peter and Keupp, Katharina and Versmold, Beatrix and Pohl, Esther and Kubisch, Christian and Grill, Sabine and Paul, Victoria and Herold, Natalie and Lichey, Nadine and Rhiem, Kerstin and Ditsch, Nina and Ruckert, Christian and Wappenschmidt, Barbara and Auber, Bernd and Rump, Andreas and Niederacher, Dieter and Haaf, Thomas and Ramser, Juliane and Dworniczak, Bernd and Engel, Christoph and Meindl, Alfons and Schmutzler, Rita K. and Hahnen, Eric},
  title     = {Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer},
  series = {Cancer Medicine},
  journal   = {Cancer Medicine},
  doi       = {10.1002/cam4.1376},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227902},
  pages     = {1349-1358},
  year      = {2018},
  abstract  = {The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5\%), followed by ATM (1.5\%) and PALB2 (1.2\%). The mutation prevalence in each of the remaining genes was 0.3\% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95\%CI: 2.67-4.94), CDH1 (OR: 17.04, 95\%CI: 3.54-82), CHEK2 (OR: 2.93, 95\%CI: 2.29-3.75), PALB2 (OR: 9.53, 95\%CI: 6.25-14.51), and TP53 (OR: 7.30, 95\%CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95\%CI: 0.73-2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2\%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors.},
  language  = {en}
}