TY  - JOUR
A1  - Dumont, Martine
A1  - Weber-Lassalle, Nana
A1  - Joly-Beauparlant, Charles
A1  - Ernst, Corinna
A1  - Droit, Arnaud
A1  - Feng, Bing-Jian
A1  - Dubois, Stéphane
A1  - Collin-Deschesnes, Annie-Claude
A1  - Soucy, Penny
A1  - Vallée, Maxime
A1  - Fournier, Frédéric
A1  - Lemaçon, Audrey
A1  - Adank, Muriel A.
A1  - Allen, Jamie
A1  - Altmüller, Janine
A1  - Arnold, Norbert
A1  - Ausems, Margreet G. E. M.
A1  - Berutti, Riccardo
A1  - Bolla, Manjeet K.
A1  - Bull, Shelley
A1  - Carvalho, Sara
A1  - Cornelissen, Sten
A1  - Dufault, Michael R.
A1  - Dunning, Alison M.
A1  - Engel, Christoph
A1  - Gehrig, Andrea
A1  - Geurts-Giele, Willemina R. R.
A1  - Gieger, Christian
A1  - Green, Jessica
A1  - Hackmann, Karl
A1  - Helmy, Mohamed
A1  - Hentschel, Julia
A1  - Hogervorst, Frans B. L.
A1  - Hollestelle, Antoinette
A1  - Hooning, Maartje J.
A1  - Horváth, Judit
A1  - Ikram, M. Arfan
A1  - Kaulfuß, Silke
A1  - Keeman, Renske
A1  - Kuang, Da
A1  - Luccarini, Craig
A1  - Maier, Wolfgang
A1  - Martens, John W. M.
A1  - Niederacher, Dieter
A1  - Nürnberg, Peter
A1  - Ott, Claus-Eric
A1  - Peters, Annette
A1  - Pharoah, Paul D. P.
A1  - Ramirez, Alfredo
A1  - Ramser, Juliane
A1  - Riedel-Heller, Steffi
A1  - Schmidt, Gunnar
A1  - Shah, Mitul
A1  - Scherer, Martin
A1  - Stäbler, Antje
A1  - Strom, Tim M.
A1  - Sutter, Christian
A1  - Thiele, Holger
A1  - van Asperen, Christi J.
A1  - van der Kolk, Lizet
A1  - van der Luijt, Rob B.
A1  - Volk, Alexander E.
A1  - Wagner, Michael
A1  - Waisfisz, Quinten
A1  - Wang, Qin
A1  - Wang-Gohrke, Shan
A1  - Weber, Bernhard H. F.
A1  - Devilee, Peter
A1  - Tavtigian, Sean
A1  - Bader, Gary D.
A1  - Meindl, Alfons
A1  - Goldgar, David E.
A1  - Andrulis, Irene L.
A1  - Schmutzler, Rita K.
A1  - Easton, Douglas F.
A1  - Schmidt, Marjanka K.
A1  - Hahnen, Eric
A1  - Simard, Jacques
T1  - Uncovering the contribution of moderate-penetrance susceptibility genes to breast cancer by whole-exome sequencing and targeted enrichment sequencing of candidate genes in women of European ancestry
JF  - Cancers
N2  - Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.
KW  - breast cancer
KW  - genetic susceptibility
KW  - whole-exome sequencing
KW  - moderate-penetrance genes
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281768
SN  - 2072-6694
VL  - 14
IS  - 14
ER  - 
TY  - JOUR
A1  - Engel, Christoph
A1  - Rhiem, Kerstin
A1  - Hahnen, Eric
A1  - Loibl, Sibylle
A1  - Weber, Karsten E.
A1  - Seiler, Sabine
A1  - Zachariae, Silke
A1  - Hauke, Jan
A1  - Wappenschmidt, Barbara
A1  - Waha, Anke
A1  - Blümcke, Britta
A1  - Kiechle, Marion
A1  - Meindl, Alfons
A1  - Niederacher, Dieter
A1  - Bartram, Claus R.
A1  - Speiser, Dorothee
A1  - Schlegelberger, Brigitte
A1  - Arnold, Norbert
A1  - Wieacker, Peter
A1  - Leinert, Elena
A1  - Gehrig, Andrea
A1  - Briest, Susanne
A1  - Kast, Karin
A1  - Riess, Olaf
A1  - Emons, Günter
A1  - Weber, Bernhard H. F.
A1  - Engel, Jutta
A1  - Schmutzler, Rita K.
T1  - Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history
JF  - BMC Cancer
N2  - Background 
There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. 

Methods
The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. 

Results
A total of 127 women with TNBC(15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1. 1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95% CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. 

Conclusions
Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
KW  - hereditary breast and ovarian cancer
KW  - BRCA1
KW  - BRCA2
KW  - triple-negative breast cancer
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226763
VL  - 18
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  - 
TY  - JOUR
A1  - Vollmuth, Christoph
A1  - Muljukov, Olga
A1  - Abu-Mugheisib, Mazen
A1  - Angermeier, Anselm
A1  - Barlinn, Jessica
A1  - Busetto, Loraine
A1  - Grau, Armin J.
A1  - Günther, Albrecht
A1  - Gumbinger, Christoph
A1  - Hubert, Nikolai
A1  - Hüttemann, Katrin
A1  - Klingner, Carsten
A1  - Naumann, Markus
A1  - Palm, Frederick
A1  - Remi, Jan
A1  - Rücker, Viktoria
A1  - Schessl, Joachim
A1  - Schlachetzki, Felix
A1  - Schuppner, Ramona
A1  - Schwab, Stefan
A1  - Schwartz, Andreas
A1  - Trommer, Adrian
A1  - Urbanek, Christian
A1  - Volbers, Bastian
A1  - Weber, Joachim
A1  - Wojciechowski, Claudia
A1  - Worthmann, Hans
A1  - Zickler, Philipp
A1  - Heuschmann, Peter U.
A1  - Haeusler, Karl Georg
A1  - Hubert, Gordian Jan
T1  - Impact of the coronavirus disease 2019 pandemic on stroke teleconsultations in Germany in the first half of 2020
JF  - European Journal of Neurology
N2  - Background and purpose
The effects of the coronavirus disease 2019 (COVID-19) pandemic on telemedical care have not been described on a national level. Thus, we investigated the medical stroke treatment situation before, during, and after the first lockdown in Germany.

Methods
In this nationwide, multicenter study, data from 14 telemedical networks including 31 network centers and 155 spoke hospitals covering large parts of Germany were analyzed regarding patients' characteristics, stroke type/severity, and acute stroke treatment. A survey focusing on potential shortcomings of in-hospital and (telemedical) stroke care during the pandemic was conducted.

Results
Between January 2018 and June 2020, 67,033 telemedical consultations and 38,895 telemedical stroke consultations were conducted. A significant decline of telemedical (p < 0.001) and telemedical stroke consultations (p < 0.001) during the lockdown in March/April 2020 and a reciprocal increase after relaxation of COVID-19 measures in May/June 2020 were observed. Compared to 2018–2019, neither stroke patients' age (p = 0.38), gender (p = 0.44), nor severity of ischemic stroke (p = 0.32) differed in March/April 2020. Whereas the proportion of ischemic stroke patients for whom endovascular treatment (14.3% vs. 14.6%; p = 0.85) was recommended remained stable, there was a nonsignificant trend toward a lower proportion of recommendation of intravenous thrombolysis during the lockdown (19.0% vs. 22.1%; p = 0.052). Despite the majority of participating network centers treating patients with COVID-19, there were no relevant shortcomings reported regarding in-hospital stroke treatment or telemedical stroke care.

Conclusions
Telemedical stroke care in Germany was able to provide full service despite the COVID-19 pandemic, but telemedical consultations declined abruptly during the lockdown period and normalized after relaxation of COVID-19 measures in Germany.
KW  - COVID-19
KW  - SARS-CoV- 2
KW  - stroke
KW  - telemedicine
KW  - survey
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259396
VL  - 28
IS  - 10
ER  - 
TY  - JOUR
A1  - Weber, Christoph
A1  - Gräf, Stephan
T1  - Eine halb so schlimme Täuschung
JF  - JURA - Juristische Ausbildung
N2  - Kein Abstract verfügbar.
KW  - Examensklausur
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195484
SN  - 1612-7021
SN  - 0170-1452
N1  - Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
VL  - 36
IS  - 1
ER  - 
TY  - JOUR
A1  - Kleinschnitz, Christoph
A1  - Niemczyk, Gabriele
A1  - Rehberg-Weber, Karin
A1  - Wernsdörfer, Colin
T1  - Interferon Beta-1a (AVONEX®) as a treatment option for untreated patients with multiple sclerosis (AXIOM): a prospective, observational study
JF  - International Journal of Molecular Sciences
N2  - The efficacy and safety of first-line disease-modifying therapies (DMT) for relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in pivotal, randomized trials, but these studies do not reflect the routine care setting where treatment gaps or switches are common. The Avonex as Treatment Option for Untreated MS Patients (AXIOM) trial assessed the efficacy of newly-initiated intramuscular interferon beta-1a (IM IFNb-1a) after a treatment-free interval, with particular consideration of the previous course of disease and therapy. The AXIOM trial was an open, 12-month, observational, non-interventional study with a retrospective and a prospective part conducted in Germany. RRMS patients with a treatment-free interval of at least three months were included and treated with IFNb-1a for up to 12 months. Relapse rate, disability progression, injection-related parameters and quality of life observed during the prospective part were compared with retrospectively-collected data. Two hundred and thirty five RRMS patients participated in AXIOM. The mean relapse rate decreased from 1.1 in the three months before baseline to 0.2 per quarter during the twelve-month observational period; the Multiple Sclerosis Functional Composite score improved during twelve months of IM IFNb-1a treatment, while the Expanded Disability Status Scale score did not change over the course of this study. Compared to previous DMTs (IM IFNb-1a, subcutaneous IFNb-1a (SC IFNb-1a), SC IFNb-1b, glatiramer acetate), the patients experienced less injection site reactions and flu-like symptoms, with a stated improved quality of life. IM IFNb-1a was effective and well accepted in RRMS patients with no or discontinued previous therapy. These results from the routine care setting may inform optimization of DMT treatment in RRMS, but need confirmation in further studies.
KW  - subcutaneous injection
KW  - therapy
KW  - trial
KW  - relapsing-remitting multiple sclerosis
KW  - injection site reactions;
KW  - efficacy
KW  - quality of life
KW  - disease-modifying therapy
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148487
VL  - 16
ER  - 
TY  - JOUR
A1  - Couch, Fergus J.
A1  - Wang, Xianshu
A1  - McGuffog, Lesley
A1  - Lee, Andrew
A1  - Olswold, Curtis
A1  - Kuchenbaecker, Karoline B.
A1  - Soucy, Penny
A1  - Fredericksen, Zachary
A1  - Barrowdale, Daniel
A1  - Dennis, Joe
A1  - Gaudet, Mia M.
A1  - Dicks, Ed
A1  - Kosel, Matthew
A1  - Healey, Sue
A1  - Sinilnikova, Olga M.
A1  - Lee, Adam
A1  - Bacot, Françios
A1  - Vincent, Daniel
A1  - Hogervorst, Frans B. L.
A1  - Peock, Susan
A1  - Stoppa-Lyonnet, Dominique
A1  - Jakubowska, Anna
A1  - Radice, Paolo
A1  - Schmutzler, Rita Katharina
A1  - Domchek, Susan M.
A1  - Piedmonte, Marion
A1  - Singer, Christian F.
A1  - Friedman, Eitan
A1  - Thomassen, Mads
A1  - Hansen, Thomas V. O.
A1  - Neuhausen, Susan L.
A1  - Szabo, Csilla I.
A1  - Blanco, Ingnacio
A1  - Greene, Mark H.
A1  - Karlan, Beth Y.
A1  - Garber, Judy
A1  - Phelan, Catherine M.
A1  - Weitzel, Jeffrey N.
A1  - Montagna, Marco
A1  - Olah, Edith
A1  - Andrulis, Irene L.
A1  - Godwin, Andrew K.
A1  - Yannoukakos, Drakoulis
A1  - Goldgar, David E.
A1  - Caldes, Trinidad
A1  - Nevanlinna, Heli
A1  - Osorio, Ana
A1  - Terry, Mary Beth
A1  - Daly, Mary B.
A1  - van Rensburg, Elisabeth J.
A1  - Hamann, Ute
A1  - Ramus, Susan J.
A1  - Toland, Amanda Ewart
A1  - Caligo, Maria A.
A1  - Olopade, Olufunmilayo I.
A1  - Tung, Nadine
A1  - Claes, Kathleen
A1  - Beattie, Mary S.
A1  - Southey, Melissa C.
A1  - Imyanitov, Evgeny N.
A1  - Tischkowitz, Marc
A1  - Janavicius, Ramunas
A1  - John, Esther M.
A1  - Kwong, Ava
A1  - Diez, Orland
A1  - Kwong, Ava
A1  - Balmaña, Judith
A1  - Barkardottir, Rosa B.
A1  - Arun, Banu K.
A1  - Rennert, Gad
A1  - Teo, Soo-Hwang
A1  - Ganz, Patricia A.
A1  - Campbell, Ian
A1  - van der Hout, Annemarie H.
A1  - van Deurzen, Carolien H. M.
A1  - Seynaeve, Caroline
A1  - Garcia, Encarna B. Gómez
A1  - van Leeuwen, Flora E.
A1  - Meijers-Heijboer, Hanne E. J.
A1  - Gille, Johannes J. P.
A1  - Ausems, Magreet G. E. M.
A1  - Blok, Marinus J.
A1  - Ligtenberg, Marjolinjin J. L.
A1  - Rookus, Matti A.
A1  - Devilee, Peter
A1  - Verhoef, Senno
A1  - van Os, Theo A. M.
A1  - Wijnen, Juul T.
A1  - Frost, Debra
A1  - Ellis, Steve
A1  - Fineberg, Elena
A1  - Platte, Radke
A1  - Evans, D. Gareth
A1  - Izatt, Luise
A1  - Eeles, Rosalind A.
A1  - Adlard, Julian
A1  - Eccles, Diana M.
A1  - Cook, Jackie
A1  - Brewer, Carole
A1  - Douglas, Fiona
A1  - Hodgson, Shirley
A1  - Morrison, Patrick J.
A1  - Side, Lucy E.
A1  - Donaldson, Alan
A1  - Houghton, Catherine
A1  - Rogers, Mark T.
A1  - Dorkins, Huw
A1  - Eason, Jacqueline
A1  - Gregory, Helen
A1  - McCann, Emma
A1  - Murray, Alex
A1  - Calender, Alain
A1  - Hardouin, Agnès
A1  - Berthet, Pascaline
A1  - Delnatte, Capucine
A1  - Nogues, Catherine
A1  - Lasset, Christine
A1  - Houdayer, Claude
A1  - Leroux,, Dominique
A1  - Rouleau, Etienne
A1  - Prieur, Fabienne
A1  - Damiola, Francesca
A1  - Sobol, Hagay
A1  - Coupier, Isabelle
A1  - Venat-Bouvet, Laurence
A1  - Castera, Laurent
A1  - Gauthier-Villars, Marion
A1  - Léoné, Mélanie
A1  - Pujol, Pascal
A1  - Mazoyer, Sylvie
A1  - Bignon, Yves-Jean
A1  - Zlowocka-Perlowska, Elzbieta
A1  - Gronwald, Jacek
A1  - Lubinski,, Jan
A1  - Durda, Katarzyna
A1  - Jaworska, Katarzyna
A1  - Huzarski, Tomasz
A1  - Spurdle, Amanda B.
A1  - Viel, Alessandra
A1  - Peissel, Bernhard
A1  - Bonanni, Bernardo
A1  - Melloni, Guilia
A1  - Ottini, Laura
A1  - Papi, Laura
A1  - Varesco, Liliana
A1  - Tibiletti, Maria Grazia
A1  - Peterlongo, Paolo
A1  - Volorio, Sara
A1  - Manoukian, Siranoush
A1  - Pensotti, Valeria
A1  - Arnold, Norbert
A1  - Engel, Christoph
A1  - Deissler, Helmut
A1  - Gadzicki, Dorothea
A1  - Gehrig, Andrea
A1  - Kast, Karin
A1  - Rhiem, Kerstin
A1  - Meindl, Alfons
A1  - Niederacher, Dieter
A1  - Ditsch, Nina
A1  - Plendl, Hansjoerg
A1  - Preisler-Adams, Sabine
A1  - Engert, Stefanie
A1  - Sutter, Christian
A1  - Varon-Mateeva, Raymenda
A1  - Wappenschmidt, Barbara
A1  - Weber, Bernhard H. F.
A1  - Arver, Brita
A1  - Stenmark-Askmalm, Marie
A1  - Loman, Niklas
A1  - Rosenquist, Richard
A1  - Einbeigi, Zakaria
A1  - Nathanson, Katherine L.
A1  - Rebbeck, Timothy R.
A1  - Blank, Stephanie V.
A1  - Cohn, David E.
A1  - Rodriguez, Gustavo C.
A1  - Small, Laurie
A1  - Friedlander, Michael
A1  - Bae-Jump, Victoria L.
A1  - Fink-Retter, Anneliese
A1  - Rappaport, Christine
A1  - Gschwantler-Kaulich, Daphne
A1  - Pfeiler, Georg
A1  - Tea, Muy-Kheng
A1  - Lindor, Noralane M.
A1  - Kaufman, Bella
A1  - Paluch, Shani Shimon
A1  - Laitman, Yael
A1  - Skytte, Anne-Bine
A1  - Gerdes, Anne-Marie
A1  - Pedersen, Inge Sokilde
A1  - Moeller, Sanne Traasdahl
A1  - Kruse, Torben A.
A1  - Jensen, Uffe Birk
A1  - Vijai, Joseph
A1  - Sarrel, Kara
A1  - Robson, Mark
A1  - Kauff, Noah
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Ozcelik, Hilmi
A1  - Ejlertsen, Bent
A1  - Nielsen, Finn C.
A1  - Jønson, Lars
A1  - Andersen, Mette K.
A1  - Ding, Yuan Chun
A1  - Steele, Linda
A1  - Foretova, Lenka
A1  - Teulé, Alex
A1  - Lazaro, Conxi
A1  - Brunet, Joan
A1  - Pujana, Miquel Angel
A1  - Mai, Phuong L.
A1  - Loud, Jennifer T.
A1  - Walsh, Christine
A1  - Lester, Jenny
A1  - Orsulic, Sandra
A1  - Narod, Steven A.
A1  - Herzog, Josef
A1  - Sand, Sharon R.
A1  - Tognazzo, Silvia
A1  - Agata, Simona
A1  - Vaszko, Tibor
A1  - Weaver, Joellen
A1  - Stravropoulou, Alexandra V.
A1  - Buys, Saundra S.
A1  - Romero, Atocha
A1  - de la Hoya, Miguel
A1  - Aittomäki, Kristiina
A1  - Muranen, Taru A.
A1  - Duran, Mercedes
A1  - Chung, Wendy K.
A1  - Lasa, Adriana
A1  - Dorfling, Cecilia M.
A1  - Miron, Alexander
A1  - Benitez, Javier
A1  - Senter, Leigha
A1  - Huo, Dezheng
A1  - Chan, Salina B.
A1  - Sokolenko, Anna P.
A1  - Chiquette, Jocelyne
A1  - Tihomirova, Laima
A1  - Friebel, Tara M.
A1  - Agnarsson, Bjarne A.
A1  - Lu, Karen H.
A1  - Lejbkowicz, Flavio
A1  - James, Paul A.
A1  - Hall, Per
A1  - Dunning, Alison M.
A1  - Tessier, Daniel
A1  - Cunningham, Julie
A1  - Slager, Susan L.
A1  - Chen, Wang
A1  - Hart, Steven
A1  - Stevens, Kristen
A1  - Simard, Jacques
A1  - Pastinen, Tomi
A1  - Pankratz, Vernon S.
A1  - Offit, Kenneth
A1  - Easton, Douglas F.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
T1  - Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
JF  - PLOS Genetics
N2  - BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
KW  - common variants
KW  - susceptibility alleles
KW  - genetic variants
KW  - modifiers
KW  - ZNF365
KW  - investigators
KW  - population
KW  - consortium
KW  - selection
KW  - subtypes
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127947
SN  - 1553-7404
VL  - 9
IS  - 3
ER  - 
TY  - JOUR
A1  - Soehnlein, Oliver
A1  - Drechsler, Maik
A1  - Döring, Yvonne
A1  - Lievens, Dirk
A1  - Hartwig, Helene
A1  - Kemmerich, Klaus
A1  - Ortega-Gómez, Almudena
A1  - Mandl, Manuela
A1  - Vijayan, Santosh
A1  - Projahn, Delia
A1  - Garlichs, Christoph D.
A1  - Koenen, Rory R.
A1  - Hristov, Mihail
A1  - Lutgens, Esther
A1  - Zernecke, Alma
A1  - Weber, Christian
T1  - Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes
JF  - EMBO Molecular Medicine
N2  - We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical \((inflammatory/Gr1^{hi})\) or non-classical \((resident/Gr1^{lo})\) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient \((Apoe^{-/-})\) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient \(Apoe^{-/-}\) mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or \(CX_3CR1\) in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment.
KW  - hypercholeterolemia
KW  - CCR2
KW  - atherosclerosis
KW  - chemokine
KW  - accumulation
KW  - subsets
KW  - inflammatory sites
KW  - fractalkine
KW  - marcophages
KW  - mobilization
KW  - monocyte
KW  - recruitment
KW  - bone-marrow
KW  - atheriosclerotic lesions
KW  - hyperlipedemic mice
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122204
SN  - 1757-4676
VL  - 5
ER  - 
TY  - JOUR
A1  - Jaite, Charlotte
A1  - Bühren, Katharina
A1  - Dahmen, Brigitte
A1  - Dempfle, Astrid
A1  - Becker, Katja
A1  - Correll, Christoph U.
A1  - Egberts, Karin M.
A1  - Ehrlich, Stefan
A1  - Fleischhaker, Christian
A1  - von Gontard, Alexander
A1  - Hahn, Freia
A1  - Kolar, David
A1  - Kaess, Michael
A1  - Legenbauer, Tanja
A1  - Renner, Tobias J.
A1  - Schulze, Ulrike
A1  - Sinzig, Judith
A1  - Thomae, Ellen
A1  - Weber, Linda
A1  - Wessing, Ida
A1  - Antony, Gisela
A1  - Hebebrand, Johannes
A1  - Föcker, Manuel
A1  - Herpertz-Dahlmann, Beate
T1  - Clinical Characteristics of Inpatients with Childhood vs. Adolescent Anorexia Nervosa
JF  - Nutrients
N2  - We aimed to compare the clinical data at first presentation to inpatient treatment of children (<14 years) vs. adolescents (≥14 years) with anorexia nervosa (AN), focusing on duration of illness before hospital admission and body mass index (BMI) at admission and discharge, proven predictors of the outcomes of adolescent AN. Clinical data at first admission and at discharge in 289 inpatients with AN (children: n = 72; adolescents: n = 217) from a German multicenter, web-based registry for consecutively enrolled patients with childhood and adolescent AN were analyzed. Inclusion criteria were a maximum age of 18 years, first inpatient treatment due to AN, and a BMI <10th BMI percentile at admission. Compared to adolescents, children with AN had a shorter duration of illness before admission (median: 6.0 months vs. 8.0 months, p = 0.004) and higher BMI percentiles at admission (median: 0.7 vs. 0.2, p = 0.004) as well as at discharge (median: 19.3 vs. 15.1, p = 0.011). Thus, in our study, children with AN exhibited clinical characteristics that have been associated with better outcomes, including higher admission and discharge BMI percentile. Future studies should examine whether these factors are actually associated with positive long-term outcomes in children.
KW  - anorexia nervosa
KW  - children
KW  - adolescents
KW  - clinical characteristics
KW  - BMI
KW  - outcome
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193160
SN  - 2072-6643
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Seegers, Joachim
A1  - Zabel, Markus
A1  - Grüter, Timo
A1  - Ammermann, Antje
A1  - Weber-Krüger, Mark
A1  - Edelmann, Frank
A1  - Gelbrich, Götz
A1  - Binder, Lutz
A1  - Herrmann-Lingen, Christoph
A1  - Gröschel, Klaus
A1  - Hasenfuß, Gerd
A1  - Feltgen, Nicolas
A1  - Pieske, Burkert
A1  - Wachter, Rolf
T1  - Natriuretic peptides for the detection of paroxysmal atrial fibrillation
JF  - Open Heart
N2  - Background and purpose: 
Silent atrial fibrillation (AF) and tachycardia (AT) are considered precursors of ischaemic stroke. Therefore, detection of paroxysmal atrial rhythm disorders is highly relevant, but is clinically challenging. We aimed to evaluate the diagnostic value of natriuretic peptide levels in the detection of paroxysmal AT/AF in a pilot study.

Methods:
Natriuretic peptide levels were analysed in two independent patient cohorts (162 patients with arterial hypertension or other cardiovascular risk factors and 82 patients with retinal vessel disease). N-terminal-pro-brain natriuretic peptide (NT-proBNP) and BNP were measured before the start of a 7-day Holter monitoring period carefully screened for AT/AF.

Results: 
244 patients were included; 16 had paroxysmal AT/AF. After excluding patients with a history of AT/AF (n=5), 14 patients had newly diagnosed AT/AF (5.8%) NT-proBNP and BNP levels were higher in patients with paroxysmal AT/AF in both cohorts: (1) 154.4 (IQR 41.7; 303.6) versus 52.8 (30.4; 178.0) pg/mL and 70.0 (31.9; 142.4) versus 43.9 (16.3; 95.2) and (2) 216.9 (201.4; 277.1) versus 90.8 (42.3–141.7) and 96.0 (54.7; 108.2) versus 29.1 (12.0; 58.1). For the detection of AT/AF episodes, NT-proBNP and BNP had an area under the curve in receiver operating characteristic analysis of 0.76 (95% CI, 0.64 to 0.88; p=0.002) and 0.75 (0.61 to 0.89; p=0.004), respectively.

Conclusions:
NT-proBNP and BNP levels are elevated in patients with silent AT/AF as compared with sinus rhythm. Thus, screening for undiagnosed paroxysmal AF using natriuretic peptide level initiated Holter monitoring may be a useful strategy in prevention of stroke or systemic embolism.
KW  - paroxysmal atrial fibrillation
KW  - ischaemic stroke
KW  - natriuretic peptide levels
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149939
VL  - 2
IS  - e000182
ER  - 
TY  - JOUR
A1  - Sepahi, Ilnaz
A1  - Faust, Ulrike
A1  - Sturm, Marc
A1  - Bosse, Kristin
A1  - Kehrer, Martin
A1  - Heinrich, Tilman
A1  - Grundman-Hauser, Kathrin
A1  - Bauer, Peter
A1  - Ossowski, Stephan
A1  - Susak, Hana
A1  - Varon, Raymonda
A1  - Schröck, Evelin
A1  - Niederacher, Dieter
A1  - Auber, Bernd
A1  - Sutter, Christian
A1  - Arnold, Norbert
A1  - Hahnen, Eric
A1  - Dworniczak, Bernd
A1  - Wang-Gorke, Shan
A1  - Gehrig, Andrea
A1  - Weber, Bernhard H. F.
A1  - Engel, Christoph
A1  - Lemke, Johannes R.
A1  - Hartkopf, Andreas
A1  - Huu Phuc, Nguyen
A1  - Riess, Olaf
A1  - Schroeder, Christopher
T1  - Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women
JF  - BMC Cancer
N2  - 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.
KW  - breast cancer
KW  - age at onset
KW  - DNA-repair genes
KW  - next-generation-sequencing
KW  - panel sequencing
KW  - extreme phenotypes
KW  - hereditary breast and ovarian cancer
KW  - BRCA1
KW  - DNA-repair
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237676
VL  - 19
ER  - 
TY  - JOUR
A1  - Gottschalk, Michael G.
A1  - Richter, Jan
A1  - Ziegler, Christiane
A1  - Schiele, Miriam A.
A1  - Mann, Julia
A1  - Geiger, Maximilian J.
A1  - Schartner, Christoph
A1  - Homola, György A.
A1  - Alpers, Georg W.
A1  - Büchel, Christian
A1  - Fehm, Lydia
A1  - Fydrich, Thomas
A1  - Gerlach, Alexander L.
A1  - Gloster, Andrew T.
A1  - Helbig-Lang, Sylvia
A1  - Kalisch, Raffael
A1  - Kircher, Tilo
A1  - Lang, Thomas
A1  - Lonsdorf, Tina B.
A1  - Pané-Farré, Christiane A.
A1  - Ströhle, Andreas
A1  - Weber, Heike
A1  - Zwanzger, Peter
A1  - Arolt, Volker
A1  - Romanos, Marcel
A1  - Wittchen, Hans-Ulrich
A1  - Hamm, Alfons
A1  - Pauli, Paul
A1  - Reif, Andreas
A1  - Deckert, Jürgen
A1  - Neufang, Susanne
A1  - Höfler, Michael
A1  - Domschke, Katharina
T1  - Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes
JF  - Translational Psychiatry
N2  - Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
KW  - human behaviour
KW  - molecular neuroscience
KW  - personalized medicine
KW  - predictive markers
KW  - psychiatric disorders
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227479
VL  - 9
ER  -