Filter and export

Publications

7 Publications matching the given criteria: (Clear all filters)
Human disease: hereditary breast ovarian cancer syndrome7
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated … in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.

Authors: Michael T. Parsons, Emma Tudini, Hongyan Li, Eric Hahnen, Barbara Wappenschmidt, Lidia Feliubadaló, Cora M. Aalfs, Simona Agata, Kristiina Aittomäki, Elisa Alducci, María Concepción Alonso-Cerezo, Norbert Arnold, Bernd Auber, Rachel Austin, Jacopo Azzollini, Judith Balmaña, Elena Barbieri, Claus R. Bartram, Ana Blanco, Britta Blümcke, Sandra Bonache, Bernardo Bonanni, Åke Borg, Beatrice Bortesi, Joan Brunet, Carla Bruzzone, Karolin Bucksch, Giulia Cagnoli, Trinidad Caldés, Almuth Caliebe, Maria A. Caligo, Mariarosaria Calvello, Gabriele L. Capone, Sandrine M. Caputo, Ileana Carnevali, Estela Carrasco, Virginie Caux-Moncoutier, Pietro Cavalli, Giulia Cini, Edward M. Clarke, Paola Concolino, Elisa J. Cops, Laura Cortesi, Fergus J. Couch, Esther Darder, Miguel de La Hoya, Michael Dean, Irmgard Debatin, Jesús Del Valle, Capucine Delnatte, Nicolas Derive, Orland Diez, Nina Ditsch, Susan M. Domchek, Véronique Dutrannoy, Diana M. Eccles, Hans Ehrencrona, Ute Enders, D. Gareth Evans, Ulrike Faust, Ute Felbor, Irene Feroce, Miriam Fine, Henrique C. R. Galvao, Gaetana Gambino, Andrea Gehrig, Francesca Gensini, Anne-Marie Gerdes, Aldo Germani, Jutta Giesecke, Viviana Gismondi, Carolina Gómez, Encarna B. Gómez Garcia, Sara González, Elia Grau, Sabine Grill, Eva Gross, Aliana Guerrieri-Gonzaga, Marine Guillaud-Bataille, Sara Gutiérrez-Enríquez, Thomas Haaf, Karl Hackmann, Thomas v. O. Hansen, Marion Harris, Jan Hauke, Tilman Heinrich, Heide Hellebrand, Karen N. Herold, Ellen Honisch, Judit Horvath, Claude Houdayer, Verena Hübbel, Silvia Iglesias, Angel Izquierdo, Paul A. James, Linda A. M. Janssen, Udo Jeschke, Silke Kaulfuß, Katharina Keupp, Marion Kiechle, Alexandra Kölbl, Sophie Krieger, Torben A. Kruse, Anders Kvist, Fiona Lalloo, Mirjam Larsen, Vanessa L. Lattimore, Charlotte Lautrup, Susanne Ledig, Elena Leinert, Alexandra L. Lewis, Joanna Lim, Markus Loeffler, Adrià López-Fernández, Emanuela Lucci-Cordisco, Nicolai Maass, Siranoush Manoukian, Monica Marabelli, Laura Matricardi, Alfons Meindl, Rodrigo D. Michelli, Setareh Moghadasi, Alejandro Moles-Fernández, Marco Montagna, Gemma Montalban, Alvaro N. Monteiro, Eva Montes, Luigi Mori, Lidia Moserle, Clemens R. Müller, Christoph Mundhenke, Nadia Naldi, Katherine L. Nathanson, Matilde Navarro, Heli Nevanlinna, Cassandra B. Nichols, Dieter Niederacher, Henriette R. Nielsen, Kai-Ren Ong, Nicholas Pachter, Edenir I. Palmero, Laura Papi, Inge Sokilde Pedersen, Bernard Peissel, Pedro Pérez-Segura, Katharina Pfeifer, Marta Pineda, Esther Pohl-Rescigno, Nicola K. Poplawski, Berardino Porfirio, Anne S. Quante, Juliane Ramser, Rui M. Reis, Françoise Revillion, Kerstin Rhiem, Barbara Riboli, Julia Ritter, Daniela Rivera, Paula Rofes, Andreas Rump, Monica Salinas, Ana María Sánchez de Abajo, Gunnar Schmidt, Ulrike Schoenwiese, Jochen Seggewiß, Ares Solanes, Doris Steinemann, Mathias Stiller, Dominique Stoppa-Lyonnet, Kelly J. Sullivan, Rachel Susman, Christian Sutter, Sean V. Tavtigian, Soo H. Teo, Alex Teulé, Mads Thomassen, Maria Grazia Tibiletti, Silvia Tognazzo, Amanda E. Toland, Eva Tornero, Therese Törngren, Sara Torres-Esquius, Angela Toss, Alison H. Trainer, Christi J. van Asperen, Marion T. van Mackelenbergh, Liliana Varesco, Gardenia Vargas-Parra, Raymonda Varon, Ana Vega, Ángela Velasco, Anne-Sophie Vesper, Alessandra Viel, Maaike P. G. Vreeswijk, Sebastian A. Wagner, Anke Waha, Logan C. Walker, Rhiannon J. Walters, Shan Wang-Gohrke, Bernhard H. F. Weber, Wilko Weichert, Kerstin Wieland, Lisa Wiesmüller, Isabell Witzel, Achim Wöckel, Emma R. Woodward, Silke Zachariae, Valentina Zampiga, Christine Zeder-Göß, Conxi Lázaro, Arcangela de Nicolo, Paolo Radice, Christoph Engel, Rita K. Schmutzler, David E. Goldgar, Amanda B. Spurdle

Date Published: 1st Sep 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Breast cancer risk in BRCA1/2 mutation carriers and noncarriers under prospective intensified surveillance.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We … determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1-56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2-19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8-6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4-12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk.

Authors: C. Engel, C. Fischer, S. Zachariae, K. Bucksch, K. Rhiem, J. Giesecke, N. Herold, B. Wappenschmidt, V. Hubbel, M. Maringa, S. Reichstein-Gnielinski, E. Hahnen, C. R. Bartram, N. Dikow, S. Schott, D. Speiser, D. Horn, E. M. Fallenberg, M. Kiechle, A. S. Quante, A. S. Vesper, T. Fehm, C. Mundhenke, N. Arnold, E. Leinert, W. Just, U. Siebers-Renelt, S. Weigel, A. Gehrig, A. Wockel, B. Schlegelberger, S. Pertschy, K. Kast, P. Wimberger, S. Briest, M. Loeffler, U. Bick, R. K. Schmutzler

Date Published: 13th May 2019

Publication Type: Not specified

Human Diseases: hereditary breast ovarian cancer syndrome

An integrative web platform for user-friendly application of risk prediction models in hereditary cancer predisposition
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Background and Objective: Predicting individual mutation and cancer risks is essential to assist genetic counsellors in clinical decision making for patients with a hereditary cancer predisposition. … Worldwide a variety of statistical models and empirical data for risk prediction have been developed and published for hereditary breast and ovarian cancer (HBOC), and hereditary non-polyposis colorectal cancer (HNPCC / Lynch syndrome, LS). However, only few models have so far been implemented in convenient and easy-to-use computer applications. We therefore aimed to develop user-friendly applications of selected HBOC and LS risk prediction models, and to make them available through the "Leipzig Health Atlas" (LHA), a web-based multifunctional platform to share research data, novel ontologies, models and software tools with the medical and scientific community. LHA is a project funded within the BMBF initiative "i:DSem – Integrative data semantics in system medicine". Methods and Results: We selected a total of six statistical models and empirical datasets relevant for HBOC and LS: 1) the Manchester Scoring System, 2) the "Mutation Frequency Explorer" of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), 3) an extended version of the Claus model, 4) MMRpredict, 5) PREMM1,2,6, and 6) PREMM5. The Manchester Scoring System allows calculation of BRCA1/2 mutation probabilities based on aggregated family history. The "Mutation Frequency Explorer" allows flexible assessment of mutation risks in BRCA1/2 and other genes for different sets of familial cancer histories based on a large dataset from the GC-HBOC. The extended Claus model (as implemented in the commercial predigree drawing software Cyrillic 2.1.3, which is no longer supported and no longer works on newer operating systems) predicts both mutation and breast cancer risks based on structured pedigree data. MMRpredict, PREMM 1,2,6, and PREMM 5 predict mutation risks in mismatch repair genes for patients from families suspected of having LS. All models were implemented using the statistical software "R" and the R-package "Shiny". "Shiny" allows the development of interactive applications by incorporating "R" with HTML and other web technologies. The Shiny apps are accessible on the website of the "Leipzig Health Atlas" (https://www.health-atlas.de) for registered researchers and genetic counselors. Conclusions: The risk prediction apps allow convenient calculation of mutation or cancer risks for an advice-seeking individual based on pedigree data or aggregated information on the familial cancer history. Target users should be specialized health professionals (physicians and genetic counselors) and scientists to ensure correct handling of the tools and careful interpretation of results.

Authors: Silke Zachariae, Sebastian Stäubert, C. Fischer, Markus Löffler, Christoph Engel

Date Published: 8th Mar 2019

Publication Type: InProceedings

Human Diseases: hereditary breast ovarian cancer syndrome, Lynch syndrome, colorectal cancer

Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

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 …c 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 \textless 0.001). gBRCA mutation risk was predicted to be \textgreater 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.

Authors: Christoph Engel, Kerstin Rhiem, Eric Hahnen, Sibylle Loibl, Karsten E. Weber, Sabine Seiler, Silke Zachariae, Jan Hauke, Barbara Wappenschmidt, Anke Waha, Britta Blümcke, Marion Kiechle, Alfons Meindl, Dieter Niederacher, Claus R. Bartram, Dorothee Speiser, Brigitte Schlegelberger, Norbert Arnold, Peter Wieacker, Elena Leinert, Andrea Gehrig, Susanne Briest, Karin Kast, Olaf Riess, Günter Emons, Bernhard H. F. Weber, Jutta Engel, Rita K. Schmutzler

Date Published: 1st Dec 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND: Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used … to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated. PATIENTS AND METHODS: Using data from 7352 German families we estimated BRCA1/2 carrier probabilities under each model and compared their discrimination and calibration. The incremental value of using pathology information in BOADICEA was assessed in a subsample of 4928 pedigrees with available data on breast tumour molecular markers oestrogen receptor, progesterone receptor and human epidermal growth factor 2. RESULTS: BRCAPRO (area under receiver operating characteristic curve (AUC)=0.80 (95% CI 0.78 to 0.81)) and BOADICEA (AUC=0.79 (0.78-0.80)), had significantly higher diagnostic accuracy than IBIS and eCLAUS (p<0.001). The AUC increased when pathology information was used in BOADICEA: AUC=0.81 (95% CI 0.80 to 0.83, p<0.001). At carrier thresholds of 10% and 15%, the net reclassification index was +3.9% and +5.4%, respectively, when pathology was included in the model. Overall, calibration was best for BOADICEA and worst for eCLAUS. With eCLAUS, twice as many mutation carriers were predicted than observed. CONCLUSIONS: Our results support the use of BRCAPRO and BOADICEA for decision making regarding genetic testing for BRCA1/2 mutations. However, model calibration has to be improved for this population. eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account.

Authors: C. Fischer, K. Kuchenbacker, C. Engel, S. Zachariae, K. Rhiem, A. Meindl, N. Rahner, N. Dikow, H. Plendl, I. Debatin, T. Grimm, D. Gadzicki, R. Flottmann, J. Horvath, E. Schrock, F. Stock, D. Schafer, I. Schwaab, C. Kartsonaki, N. Mavaddat, B. Schlegelberger, A. C. Antoniou, R. Schmutzler

Date Published: 9th Apr 2013

Publication Type: Not specified

Human Diseases: hereditary breast ovarian cancer syndrome

The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION While it has been reported that the risk of contralateral breast cancer in patients from BRCA1 or BRCA2 positive families is elevated, little is known about contralateral breast cancer …r risk in patients from high risk families that tested negative for BRCA1/2 mutations. METHODS A retrospective, multicenter cohort study was performed from 1996 to 2011 and comprised 6,235 women with unilateral breast cancer from 6,230 high risk families that had tested positive for BRCA1 (n = 1,154) or BRCA2 (n = 575) mutations or tested negative (n = 4,501). Cumulative contralateral breast cancer risks were calculated using the Kaplan-Meier product-limit method and were compared between groups using the log-rank test. Cox regression analysis was applied to assess the impact of the age at first breast cancer and the familial history stratified by mutation status. RESULTS The cumulative risk of contralateral breast cancer 25 years after first breast cancer was 44.1% (95%CI, 37.6% to 50.6%) for patients from BRCA1 positive families, 33.5% (95%CI, 22.4% to 44.7%) for patients from BRCA2 positive families and 17.2% (95%CI, 14.5% to 19.9%) for patients from families that tested negative for BRCA1/2 mutations. Younger age at first breast cancer was associated with a higher risk of contralateral breast cancer. For women who had their first breast cancer before the age of 40 years, the cumulative risk of contralateral breast cancer after 25 years was 55.1% for BRCA1, 38.4% for BRCA2, and 28.4% for patients from BRCA1/2 negative families. If the first breast cancer was diagnosed at the age of 50 or later, 25-year cumulative risks were 21.6% for BRCA1, 15.5% for BRCA2, and 12.9% for BRCA1/2 negative families. CONCLUSIONS Contralateral breast cancer risk in patients from high risk families that tested negative for BRCA1/2 mutations is similar to the risk in patients with sporadic breast cancer. Thus, the mutation status should guide decision making for contralateral mastectomy.

Authors: Kerstin Rhiem, Christoph Engel, Monika Graeser, Silke Zachariae, Karin Kast, Marion Kiechle, Nina Ditsch, Wolfgang Janni, Christoph Mundhenke, Michael Golatta, Dominic Varga, Sabine Preisler-Adams, Tilman Heinrich, Ulrich Bick, Dorothea Gadzicki, Susanne Briest, Alfons Meindl, Rita K. Schmutzler

Date Published: 1st Dec 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

BRCA1/2 testing: uptake, phenocopies, and strategies to improve detection rates in initially negative families
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

In families with clustering of breast and ovarian cancer, molecular testing of the major susceptibility genes BRCA1/2 helps to identify patients with disease mutations and healthy persons at high risk … who can participate in targeted intervention programs. We investigated 5559 families from the German Consortium for Hereditary Breast and Ovarian Cancer included between 1997 and 2008 and treated under clinical routine conditions. In each family an index patient/person had been screened for deleterious mutations in BRCA1/2. Healthy relatives agreed to predictive testing in 888 of 1520 BRCA1/2 mutation-positive families (58%). Of 2646 eligible unaffected first-degree relatives 1143 decided to be tested (43%). In 325 families with BRCA1/2-positive index patients one related BC/OC patient was tested and 39 (12.0%; 95% confidence interval: 8.7-16.0%) discrepant cases found. A second related individual was screened in 163 of 3388 (4.9%) families with BRCA1/2-negative index patient and in eight families a BRCA1/2 mutation was found. In BRCA1/2 mutation-positive families, BC/OC patients lacking the familial mutation have to be expected at a rather high rate. In families with BRCA1/2-negative index patient we recommend a second screening if another patient with a high probability of carrying a BRCA1/2 mutation is available.

Authors: C. Fischer, C. Engel, C. Sutter, S. Zachariae, R. Schmutzler, A. Meindl, S. Heidemann, T. Grimm, T. O. Goecke, I. Debatin, D. Horn, P. Wieacker, D. Gadzicki, K. Becker, D. Schäfer, F. Stock, T. Voigtländer

Date Published: 1st Nov 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Navigate

Health Atlas - Local Data Hub/Leipzig

The Health Atlas - Local Data Hub/Leipzig is an alliance of medical ontologists, medical systems biologists and clinical trials groups to design and implement a multi-functional and quality-assured atlas. It provides models, data and metadata on specific use cases from medical research fields.

Registered Repository

re3data.org Badge
Powered by
 (v.1.13.0-master)
Health Atlas | Funding and Programmes | Credits | Terms & Conditions | Privacy Policy | Imprint
Copyright © 2008 - 2021 The University of Manchester and HITS gGmbH
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig

By continuing to use this site you agree to the use of cookies