TY - THES A1 - Schmidt, Barbara T1 - Taking your chances: risk behavior and its relation to arousal, framing and motivation T1 - Die eigenen Chancen ergreifen: Risikoverhalten und dessen Beziehung zu Arousal, Framing und Motivation N2 - Human risk behavior is the subject of growing research in the field of psychology as well as economics. One central topic is the influence of psychological variables on risk behavior. Studies contained in this work investigated the impact of arousal, framing and motivation on risk behavior. Arousal can on the one hand be a temporarily stable trait and on the other hand a situation-dependent variable. We showed that low trait arousal, measured via resting heart rate, predicted risky behavior. After physical exercise, state arousal was heightened in the experiment. Participants tended to act less risky after physical exercise. Taken together, the results suggest an inverse relation of arousal and risk behavior. Most studies investigating risk behavior employ a payment method that we call pay-one method: although the gambles that are used consist of many trials, only one trial is paid out. We investigated the effect of the payment method on risk behavior by employing both the pay-one and a pay-all method, which pays out all trials, in a within-subjects design. We found that participants acted about 10% less risky in the pay-one condition compared to the pay-all condition. This result suggests that risk-aversion is over-estimated in common risk paradigms that use the pay-one method. When we worked on a hard task before, we like to engage in a more likable task afterwards. That observation led to the general classification of tasks in want-to and have-to tasks. Our body system strives towards a balance between those two task types in the sense of a homeostasis. We assessed event-related potentials (ERPs) in a risk game that we treated as a want-to task. When participants worked on a difficult have-to task before, amplitudes of the ERP-components in the risk game were raised compared to a condition where participants worked on an easy task before. We conclude that the motivation shift towards a want-to task after a have-to task can be assessed via ERP amplitudes. In conclusion, it was shown that arousal, framing and motivation are important psychological variables that influence risk behavior. The specific mechanisms of these influences have been investigated and discussed. N2 - Menschliches Risikoverhalten ist zunehmend Gegenstand psychologischer und ökonomischer Forschung. Eine zentrale Rolle spielt dabei der Einfluss psychologischer Variablen auf Risikoverhalten. Die in dieser Arbeit vorgestellten Studien untersuchen den Einfluss von physiologischer Erregung, Framing und Motivation auf Risikoverhalten. Physiologische Erregung kann einerseits als zeitlich stabile Eigenschaft, andererseits als situationsabhängige Variable gesehen werden. Wir konnten zeigen, dass niedrige zeitlich stabile physiologische Erregung, die über die Ruhe-Herzrate gemessen wurde, riskantes Verhalten vorhersagte. Nach körperlichem Training war die physiologische Erregung der Versuchspersonen im Experiment kurzzeitig erhöht. Die Versuchspersonen tendierten dazu, nach diesem Training weniger riskant zu handeln. Zusammengenommen legen die Ergebnisse nahe, dass eine inverse Relation zwischen physiologischer Erregung und Risikoverhalten vorliegt. Die meisten Studien, die sich mit Risikoverhalten befassen, verwenden die sogenannte pay-one Auszahlungsmethode: In Risikospielen, die aus vielen Durchgängen bestehen, wird nur ein Durchgang des gesamten Risikospiels ausbezahlt. Wir untersuchten den Effekt der Auszahlungsmethode auf das Risikoverhalten, indem wir sowohl die pay-one Methode als auch die pay-all Methode, bei der die Gewinne aller Durchgänge ausbezahlt werden, in einem Zwischensubjekt-Design verwendeten. Wir fanden heraus, dass die Versuchspersonen in der pay-one Bedingung etwa 10% weniger riskant handelten, verglichen mit der pay-all Bedingung. Dieses Ergebnis legt nahe, dass die Risiko-Aversion in Paradigmen, die die pay-one Methode verwenden, überschätzt wird. Nachdem wir an einer schwierigen Aufgabe gearbeitet haben, sehnen wir uns nach einer angenehmeren Aufgabe. Diese Beobachtung führte zu einer generellen Unterscheidung von want-to und have-to Aufgaben. Unser Körper strebt nach einem Gleichgewicht zwischen diesen beiden Aufgabentypen im Sinne einer Homöostase. Wir erfassten ereigniskorrelierte Potentiale (ERPs) durch das Elektroencephalogramm in einem Risikospiel, das wir als want-to Aufgabe verwendeten. Wenn Versuchspersonen vorher eine schwere Aufgabe bearbeitet hatten, waren die Amplituden der ERP- Komponenten im Risikospiel erhöht im Vergleich zu einer Bedingung, in der die Versuchspersonen vorher eine einfache Aufgabe bearbeitet hatten. Wir schlussfolgern, dass die Motivationsänderung nach einer have-to Aufgabe in Richtung einer want-to Aufgabe mit Hilfe von ERP Amplituden erfasst werden kann. Zusammenfassend wurde gezeigt, dass physiologische Erregung, Framing und Motivation wichtige psychologische Variablen sind, die Risikoverhalten beeinflussen. Die spezifischen Wirkungsweisen dieser Einflüsse wurden untersucht und diskutiert. KW - Risikoverhalten KW - Motivation KW - arousal KW - framing KW - risk behavior Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-107149 ER - TY - JOUR A1 - Sonnenschein-van der Voort, Agnes M. M. A1 - Arends, Lidia R. A1 - de Jongste, Johan C. A1 - Annesi-Maesano, Isabella A1 - Arshad, S. Hasan A1 - Barros, Henrique A1 - Basterrechea, Mikel A1 - Bisgaard, Hans A1 - Chatzi, Leda A1 - Corpeleijn, Eva A1 - Correia, Sofia A1 - Craig, Leone C. A1 - Devereux, Graham A1 - Dogaru, Cristian A1 - Dostal, Miroslav A1 - Duchen, Karel A1 - Eggesbø, Merete A1 - van der Ent, C. Kors A1 - Fantini, Maria P. A1 - Forastiere, Francesco A1 - Frey, Urs A1 - Gehring, Ulrike A1 - Gori, Davide A1 - van der Gugten, Anne C. A1 - Hanke, Wojciech A1 - Henderson, A. John A1 - Heude, Barbara A1 - Iñiguez, Carmen A1 - Inskip, Hazel M. A1 - Keil, Thomas A1 - Kelleher, Cecily C. A1 - Kogevinas, Manolis A1 - Kreiner-Møller, Eskil A1 - Kuehni, Claudia E. A1 - Küpers, Leanne K. A1 - Lancz, Kinga A1 - Larsen, Pernille S. A1 - Lau, Susanne A1 - Ludvigsson, Johnny A1 - Mommers, Monique A1 - Andersen, Anne-Marie Nybo A1 - Palkovicova, Lubica A1 - Pike, Katherine C. A1 - Pizzi, Constanza A1 - Polanska, Kinga A1 - Porta, Daniela A1 - Richiardi, Lorenzo A1 - Roberts, Graham A1 - Schmidt, Anne A1 - Sram, Radim J. A1 - Sunyer, Jordi A1 - Thijs, Carel A1 - Torrent, Maties A1 - Viljoen, Karien A1 - Wijga, Alet H. A1 - Vrijheid, Martine A1 - Jaddoe, Vincent W. V. A1 - Duijts, Liesbeth T1 - Preterm birth, infant weight gain, and childhood asthma risk: A meta-analysis of 147,000 European children JF - The Journal of Allergy and Clinical Immunology N2 - Background Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results. Objectives We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years). Methods First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age <37 weeks) and low birth weight (<2500 g) with childhood asthma outcomes. Results Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P < .05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27). Conclusion Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weight with childhood asthma were largely explained by gestational age at birth." KW - gestational age KW - low birth weight KW - infant growth KW - wheezing KW - asthma KW - epidemiology KW - cohort studies KW - children Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120714 VL - 133 IS - 5 ER - TY - JOUR A1 - Wohlfarth, Carolin A1 - Schmitteckert, Stefanie A1 - Härtle, Janina D. A1 - Houghton, Lesley A. A1 - Dweep, Harsh A1 - Fortea, Marina A1 - Assadi, Ghazaleh A1 - Braun, Alexander A1 - Mederer, Tanja A1 - Pöhner, Sarina A1 - Becker, Philip P. A1 - Fischer, Christine A1 - Granzow, Martin A1 - Mönnikes, Hubert A1 - Mayer, Emeran A. A1 - Sayuk, Gregory A1 - Boeckxstaens, Guy A1 - Wouters, Mira M. A1 - Simrén, Magnus A1 - Lindberg, Greger A1 - Ohlsson, Bodil A1 - Schmidt, Peter Thelin A1 - Dlugosz, Aldona A1 - Agreus, Lars A1 - Andreasson, Anna A1 - D'Amato, Mauro A1 - Burwinkel, Barbara A1 - Bermejo, Justo Lorenzo A1 - Röth, Ralph A1 - Lasitschka, Felix A1 - Vicario, Maria A1 - Metzger, Marco A1 - Santos, Javier A1 - Rappold, Gudrun A. A1 - Martinez, Cristina A1 - Niesler, Beate T1 - miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome JF - Scientific Reports N2 - Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene \(HTR4\) to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms \({HTR4b/i}\) and putatively impairs \(HTR4\) expression. Subsequent miRNA profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. \(In\) \(vitro\) assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform \(HTR4b\_2\) lacking two of the three miRNA binding sites escapes miR-16/103/107 regulationin SNP carriers. We provide the first evidence that \(HTR4\) expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or bydiminished levels of miR-16 and miR-103 suggesting that \(HTR4\) might be involved in the development of IBS-D. KW - Medicine KW - Gene regulation KW - Irritable bowel syndrome Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173478 VL - 7 ER - TY - JOUR A1 - Scheer, Ulrich A1 - Schmidt-Zachmann, Marion S. A1 - Hügle, Barbara A1 - Franke, Werner W. T1 - Identification and localization of a novel nucleolar protein of a high molecular weight by a monoclonal antibody N2 - A monoclonal murine antibody (No-I 14) is described which reacts specifically with a polypeptide of molecular weight (M,) 180000 present in low-speed nuclear pellets from oocytes and somatic cells of Xenopus laevis and X. borealis and in isolated amplified nucleoli. Two-dimensional gel electrophoresis has revealed the acidic nature of this polypeptide (isoelectric at pH of ca 4.2 in the presence of 9.5 M urea). A relatively large proportion of the protein is extracted at elevated ionic strength( i.e., at 0.4-0.5 M alkali salt) in a form sedimenting at approx. 7-8S , compatible with a monomeric state. It is also extracted by digestion with RNase but not with DNase. In immunofluorescence microscopy, antibody No-114 stains intensely nucleoli of oocytes and all somatic cells examined , including the residual nucleolar structure of Xenopus erythrocytes which are transcriptionally inactive. During mitosis the antigen does not remain associated with the nucleolar organizer regions (NOR) of chromosomes but is released and dispersed over the cytoplasm until telophase when it re-associates with the reforming interphase nucleoli. At higher resolution the immunofluorescent region is often resolved into a number of distinct subnucleolar components of varied size and shape. Immunoelectron microscopy using colloidal gold-coupled secondary antibodies reveals that the M, 180000 protein is confined to the dense fibrillar component of the nucleolus. This conclusion is also supported by its localization in the fibrillar part of segregated nucleoli of cells treated with actinomycin D. We conclude that nucleoli contain a prominent protein of M, 180000 which contributes to the general structure of the dense fibrillar component of the interphase nucleolus , independent of its specific transcriptional activity. Y1 - 1984 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-39786 ER - TY - JOUR A1 - Bielaszewska, Martina A1 - Schiller, Roswitha A1 - Lammers, Lydia A1 - Bauwens, Andreas A1 - Fruth, Angelika A1 - Middendorf, Barbara A1 - Schmidt, M. Alexander A1 - Tarr, Phillip I. A1 - Dobrindt, Ulrich A1 - Karch, Helge A1 - Mellmann, Alexander T1 - Heteropathogenic virulence and phylogeny reveal phased pathogenic metamorphosis in Escherichia coli O2:H6 JF - EMBO Molecular Medicine N2 - Extraintestinal pathogenic and intestinal pathogenic (diarrheagenic) Escherichia coli differ phylogenetically and by virulence profiles. Classic theory teaches simple linear descent in this species, where non-pathogens acquire virulence traits and emerge as pathogens. However, diarrheagenic Shiga toxin-producing E.coli (STEC) O2:H6 not only possess and express virulence factors associated with diarrheagenic and uropathogenic E.coli but also cause diarrhea and urinary tract infections. These organisms are phylogenetically positioned between members of an intestinal pathogenic group (STEC) and extraintestinal pathogenic E.coli. STEC O2:H6 is, therefore, a 'heteropathogen,' and the first such hybrid virulent E.coli identified. The phylogeny of these E.coli and the repertoire of virulence traits they possess compel consideration of an alternate view of pathogen emergence, whereby one pathogroup of E.coli undergoes phased metamorphosis into another. By understanding the evolutionary mechanisms of bacterial pathogens, rational strategies for counteracting their detrimental effects on humans can be developed. KW - phased metamorphosis KW - phylogeny KW - heteropathogenicity KW - Shiga toxin-producing Escherichia coli KW - hemolytic-uremic syndrome KW - urinary-tract-infection KW - cytolethal distending toxin KW - shiga toxin KW - Crohns-disease KW - outbreak KW - genes KW - island KW - strains KW - parallel evolution KW - uropathogenic Escherichia coli Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117254 SN - 1757-4684 VL - 6 IS - 3 ER - TY - JOUR A1 - Kimpel, Otilia A1 - Schindler, Paul A1 - Schmidt-Pennington, Laura A1 - Altieri, Barbara A1 - Megerle, Felix A1 - Haak, Harm A1 - Pittaway, James A1 - Dischinger, Ulrich A1 - Quinkler, Marcus A1 - Mai, Knut A1 - Kroiss, Matthias A1 - Polat, Bülent A1 - Fassnacht, Martin T1 - Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma JF - British Journal of Cancer N2 - Background International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. Methods We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. Primary endpoint: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. Results In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50–60 Gy (n = 20) or 20–49 Gy (n = 69), stereotactic body RT of 35–50 Gy (SBRT) (n = 36), or brachytherapy of 12–25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0–148.6). In comparison to cRT\(_{20-49Gy}\), tTTP was significantly longer for cRT\(_{50-60Gy}\) (multivariate adjusted HR 0.10; 95% CI 0.03–0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12–0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22–1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. Conclusions This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC. KW - adrenal tumours KW - adrenocortical carcinoma (ACC) KW - radiotherapy (RT) Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324411 VL - 128 IS - 4 ER - TY - JOUR A1 - Herpin, Amaury A1 - Adolfi, Mateus C. A1 - Nicol, Barbara A1 - Hinzmann, Maria A1 - Schmidt, Cornelia A1 - Klughammer, Johanna A1 - Engel, Mareen A1 - Tanaka, Minoru A1 - Guiguen, Yann A1 - Schartl, Manfred T1 - Divergent Expression Regulation of Gonad Development Genes in Medaka Shows Incomplete Conservation of the Downstream Regulatory Network of Vertebrate Sex Determination JF - Molecular Biology and Evolution N2 - Genetic control of male or female gonad development displays between different groups of organisms a remarkable diversity of “master sex-determining genes” at the top of the genetic hierarchies, whereas downstream components surprisingly appear to be evolutionarily more conserved. Without much further studies, conservation of sequence has been equalized to conservation of function. We have used the medaka fish to investigate the generality of this paradigm. In medaka, the master male sex-determining gene is dmrt1bY, a highly conserved downstream regulator of sex determination in vertebrates. To understand its function in orchestrating the complex gene regulatory network, we have identified targets genes and regulated pathways of Dmrt1bY. Monitoring gene expression and interactions by transgenic fluorescent reporter fish lines, in vivo tissue-chromatin immunoprecipitation and in vitro gene regulation assays revealed concordance but also major discrepancies between mammals and medaka, notably amongst spatial, temporal expression patterns and regulations of the canonical Hedgehog and R-spondin/Wnt/Follistatin signaling pathways. Examination of Foxl2 protein distribution in the medaka ovary defined a new subpopulation of theca cells, where ovarian-type aromatase transcriptional regulation appears to be independent of Foxl2. In summary, these data show that the regulation of the downstream regulatory network of sex determination is less conserved than previously thought. KW - gonadal development KW - divergent expression regulation KW - gene regulatory network evolution KW - adaptive evolution Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132262 VL - 30 IS - 10 ER - TY - JOUR A1 - Kroeber, Jana A1 - Wenger, Barbara A1 - Schwegler, Manuela A1 - Daniel, Christoph A1 - Schmidt, Manfred A1 - Djuzenova, Cholpon S A1 - Polat, Bülent A1 - Flentje, Michael A1 - Fietkau, Rainer A1 - Distel, Luitpold V. T1 - Distinct increased outliers among 136 rectal cancer patients assessed by \(\gamma\)H2AX JF - Radiation Oncology N2 - Background: In recent years attention has focused on \(\gamma\)H2AX as a very sensitive double strand break indicator. It has been suggested that \(\gamma\)H2AX might be able to predict individual radiosensitivity. Our aim was to study the induction and repair of DNA double strand breaks labelled by \(\gamma\)H2AX in a large cohort. Methods: In a prospective study lymphocytes of 136 rectal cancer (RC) patients and 59 healthy individuals were ex vivo irradiated (IR) and initial DNA damage was compared to remaining DNA damage after 2 Gy and 24 hours repair time and preexisting DNA damage in unirradiated lymphocytes. Lymphocytes were immunostained with anti-\(\gamma\)H2AX antibodies and microscopic images with an extended depth of field were acquired. \(\gamma\)H2AX foci counting was performed using a semi-automatic image analysis software. Results: Distinct increased values of preexisting and remaining \(\gamma\)H2AX foci in the group of RC patients were found compared to the healthy individuals. Additionally there are clear differences within the groups and there are outliers in about 12% of the RC patients after ex vivo IR. Conclusions: The \(\gamma\)H2AX assay has the capability to identify a group of outliers which are most probably patients with increased radiosensitivity having the highest risk of suffering radiotherapy-related late sequelae. KW - histone H2AX KW - blood lymphocytes KW - in vivo KW - foci KW - individual radiosensitivity KW - rectal cancer KW - radiotherapy KW - DNA double strand breaks KW - phosphorylation KW - neck cancer KW - oral mucositis KW - DNA damage KW - radiosensitivity KW - repair KW - \(\gamma\)h2ax Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144085 VL - 10 IS - 36 ER - 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 -