TY - JOUR A1 - Berendzen, Kenneth W. A1 - Weiste, Christoph A1 - Wanke, Dierk A1 - Kilian, Joachim A1 - Harter, Klaus A1 - Dröge-Laser, Wolfgang T1 - Bioinformatic cis-element analyses performed in Arabidopsis and rice disclose bZIP- and MYB-related binding sites as potential AuxRE-coupling elements in auxin-mediated transcription N2 - Background: In higher plants, a diverse array of developmental and growth-related processes is regulated by the plant hormone auxin. Recent publications have proposed that besides the well-characterized Auxin Response Factors (ARFs) that bind Auxin Response Elements (AuxREs), also members of the bZIP- and MYB-transcription factor (TF) families participate in transcriptional control of auxin-regulated genes via bZIP Response Elements (ZREs) or Myb Response Elements (MREs), respectively. Results: Applying a novel bioinformatic algorithm, we demonstrate on a genome-wide scale that singular motifs or composite modules of AuxREs, ZREs, MREs but also of MYC2 related elements are significantly enriched in promoters of auxin-inducible genes. Despite considerable, species-specific differences in the genome structure in terms of the GC content, this enrichment is generally conserved in dicot (Arabidopsis thaliana) and monocot (Oryza sativa) model plants. Moreover, an enrichment of defined composite modules has been observed in selected auxin-related gene families. Consistently, a bipartite module, which encompasses a bZIP-associated G-box Related Element (GRE) and an AuxRE motif, has been found to be highly enriched. Making use of transient reporter studies in protoplasts, these findings were experimentally confirmed, demonstrating that GREs functionally interact with AuxREs in regulating auxin-mediated transcription. Conclusions: Using genome-wide bioinformatic analyses, evolutionary conserved motifs have been defined which potentially function as AuxRE-dependent coupling elements to establish auxin-specific expression patterns. Based on these findings, experimental approaches can be designed to broaden our understanding of combinatorial, auxin-controlled gene regulation. KW - Arabidopsis KW - Cis-elements KW - cis-element modules KW - Auxin-regulated transcription KW - AuxRE KW - bZIP KW - MYB KW - MYC Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75138 ER - TY - JOUR A1 - Harter, Philipp A1 - Hauke, Jan A1 - Heitz, Florian A1 - Reuss, Alexander A1 - Kommoss, Stefan A1 - Marmé, Frederik A1 - Heimbach, André A1 - Prieske, Katharina A1 - Richters, Lisa A1 - Burges, Alexander A1 - Neidhardt, Guido A1 - de Gregorio, Nikolaus A1 - El-Balat, Ahmed A1 - Hilpert, Felix A1 - Meier, Werner A1 - Kimmig, Rainer A1 - Kast, Karin A1 - Sehouli, Jalid A1 - Baumann, Klaus A1 - Jackisch, Christian A1 - Park-Simon, Tjoung-Won A1 - Hanker, Lars A1 - Kröber, Sandra A1 - Pfisterer, Jacobus A1 - Gevensleben, Heidrun A1 - Schnelzer, Andreas A1 - Dietrich, Dimo A1 - Neunhöffer, Tanja A1 - Krockenberger, Mathias A1 - Brucker, Sara Y. A1 - Nürnberg, Peter A1 - Thiele, Holger A1 - Altmüller, Janine A1 - Lamla, Josefin A1 - Elser, Gabriele A1 - du Bois, Andreas A1 - Hahnen, Eric A1 - Schmutzler, Rita T1 - Prevalence of deleterious germline variants in risk genes including \(BRCA1/2\) in consecutive ovarian cancer patients (AGO-TR-1) JF - PLoS ONE N2 - Background Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in \(BRCA1/2\) in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated. Methods Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (\(ATM\), \(BRCA1\), \(BRCA2\), \(CDH1\), \(CHEK2\), \(MLH1\), \(MSH2\), \(MSH6\), \(NBN\), \(PMS2\), \(PTEN\), \(PALB2\), \(RAD51C\), \(RAD51D\), \(STK11\), \(TP53\)) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history. Results In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the \(BRCA1\) (15.5%), \(BRCA2\) (5.5%), \(RAD51C\) (2.5%) and \(PALB2\) (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in \(BRCA1/2\) (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients \(\geq\)60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for \(BRCA1/2\) would miss in our series more than 5% of the patients with a deleterious variant in established risk genes. Conclusions 26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to \(BRCA1/2\) seems to be not sufficient. KW - medicine KW - Genetic causes of cancer KW - ovarian cancer KW - cancer risk factors KW - histology KW - cancer detection and diagnosis KW - breast cancer KW - genetic testing KW - human genetics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173553 VL - 12 IS - 10 ER -