@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{GroebnerWorstWeischenfeldtetal.2018,
  author    = {Gr{\"o}bner, Susanne N. and Worst, Barbara C. and Weischenfeldt, Joachim and Buchhalter, Ivo and Kleinheinz, Kortine and Rudneva, Vasilisa A. and Johann, Pascal D. and Balasubramanian, Gnana Prakash and Segura-Wang, Maia and Brabetz, Sebastian and Bender, Sebastian and Hutter, Barbara and Sturm, Dominik and Pfaff, Elke and H{\"u}bschmann, Daniel and Zipprich, Gideon and Heinold, Michael and Eils, J{\"u}rgen and Lawerenz, Christian and Erkek, Serap and Lambo, Sander and Waszak, Sebastian and Blattmann, Claudia and Borkhardt, Arndt and Kuhlen, Michaela and Eggert, Angelika and Fulda, Simone and Gessler, Manfred and Wegert, Jenny and Kappler, Roland and Baumhoer, Daniel and Stefan, Burdach and Kirschner-Schwabe, Renate and Kontny, Udo and Kulozik, Andreas E. and Lohmann, Dietmar and Hettmer, Simone and Eckert, Cornelia and Bielack, Stefan and Nathrath, Michaela and Niemeyer, Charlotte and Richter, G{\"u}nther H. and Schulte, Johannes and Siebert, Reiner and Westermann, Frank and Molenaar, Jan J. and Vassal, Gilles and Witt, Hendrik and Burkhardt, Birgit and Kratz, Christian P. and Witt, Olaf and van Tilburg, Cornelis M. and Kramm, Christof M. and Fleischhack, Gudrun and Dirksen, Uta and Rutkowski, Stefan and Fr{\"u}hwald, Michael and Hoff, Katja von and Wolf, Stephan and Klingebeil, Thomas and Koscielniak, Ewa and Landgraf, Pablo and Koster, Jan and Resnick, Adam C. and Zhang, Jinghui and Liu, Yanling and Zhou, Xin and Waanders, Angela J. and Zwijnenburg, Danny A. and Raman, Pichai and Brors, Benedikt and Weber, Ursula D. and Northcott, Paul A. and Pajtler, Kristian W. and Kool, Marcel and Piro, Rosario M. and Korbel, Jan O. and Schlesner, Matthias and Eils, Roland and Jones, David T. W. and Lichter, Peter and Chavez, Lukas and Zapatka, Marc and Pfister, Stefan M.},
  title     = {The landscape of genomic alterations across childhood cancers},
  series = {Nature},
  volume    = {555},
  journal   = {Nature},
  organization    = {ICGC PedBrain-Seq Project, ICGC MMML-Seq Project,},
  doi       = {10.1038/nature25480},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229579},
  pages     = {321-327},
  year      = {2018},
  abstract  = {Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8\% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50\% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.},
  language  = {en}
}