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11 Publications matching the given criteria: (Clear all filters)
Published year: 201811
BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

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 \textless 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99-59.66, P \textless 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.

Authors: Nana Weber-Lassalle, Jan Hauke, Juliane Ramser, Lisa Richters, Eva Groß, Britta Blümcke, Andrea Gehrig, Anne-Karin Kahlert, Clemens R. Müller, Karl Hackmann, Ellen Honisch, Konstantin Weber-Lassalle, Dieter Niederacher, Julika Borde, Holger Thiele, Corinna Ernst, Janine Altmüller, Guido Neidhardt, Peter Nürnberg, Kristina Klaschik, Christopher Schroeder, Konrad Platzer, Alexander E. Volk, Shan Wang-Gohrke, Walter Just, Bernd Auber, Christian Kubisch, Gunnar Schmidt, Judit Horvath, Barbara Wappenschmidt, Christoph Engel, Norbert Arnold, Bernd Dworniczak, Kerstin Rhiem, Alfons Meindl, Rita K. Schmutzler, Eric Hahnen

Date Published: 1st Dec 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Diagnosis of Li-Fraumeni Syndrome: Differentiating TP53 germline mutations from clonal hematopoiesis: Results of the observational AGO-TR1 trial
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The Li-Fraumeni cancer predisposition syndrome (LFS1) presents with a variety of tumor types and the TP53 gene is covered by most diagnostic cancer gene panels. We demonstrate that deleterious TP53 … variants identified in blood-derived DNA of 523 patients with ovarian cancer (AGO-TR1 trial) were not causal for the patients’ ovarian cancer in three out of six TP53-positive cases. In three out of six patients, deleterious TP53 mutations were identified with low variant fractions in blood-derived DNA but not in the tumor of the patient seeking advice. The analysis of the TP53 and PPM1D genes, both intimately involved in chemotherapy-induced and/or age-related clonal hematopoiesis (CH), in 523 patients and 1,053 age-matched female control individuals revealed that CH represents a frequent event following chemotherapy, affecting 26 of the 523 patients enrolled (5.0%). Considering that TP53 mutations may arise from chemotherapy-induced CH, our findings help to avoid false-positive genetic diagnoses of LFS1.

Authors: Konstantin Weber-Lassalle, Philipp Harter, Jan Hauke, Corinna Ernst, Stefan Kommoss, Frederik Marmé, Nana Weber-Lassalle, Katharina Prieske, Dimo Dietrich, Julika Borde, Esther Pohl-Rescigno, Alexander Reuss, Beyhan Ataseven, Christoph Engel, Julia C. Stingl, Rita K. Schmutzler, Eric Hahnen

Date Published: 1st Dec 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Performance of in silico prediction tools for the classification of rare BRCA1/2 missense variants in clinical diagnostics
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The use of next-generation sequencing approaches in clinical diagnostics has led to a tremendous increase in data and a vast number of variants of uncertain significance that require …e interpretation. Therefore, prediction of the effects of missense mutations using in silico tools has become a frequently used approach. Aim of this study was to assess the reliability of in silico prediction as a basis for clinical decision making in the context of hereditary breast and/or ovarian cancer. METHODS We tested the performance of four prediction tools (Align-GVGD, SIFT, PolyPhen-2, MutationTaster2) using a set of 236 BRCA1/2 missense variants that had previously been classified by expert committees. However, a major pitfall in the creation of a reliable evaluation set for our purpose is the generally accepted classification of BRCA1/2 missense variants using the multifactorial likelihood model, which is partially based on Align-GVGD results. To overcome this drawback we identified 161 variants whose classification is independent of any previous in silico prediction. In addition to the performance as stand-alone tools we examined the sensitivity, specificity, accuracy and Matthews correlation coefficient (MCC) of combined approaches. RESULTS PolyPhen-2 achieved the lowest sensitivity (0.67), specificity (0.67), accuracy (0.67) and MCC (0.39). Align-GVGD achieved the highest values of specificity (0.92), accuracy (0.92) and MCC (0.73), but was outperformed regarding its sensitivity (0.90) by SIFT (1.00) and MutationTaster2 (1.00). All tools suffered from poor specificities, resulting in an unacceptable proportion of false positive results in a clinical setting. This shortcoming could not be bypassed by combination of these tools. In the best case scenario, 138 families would be affected by the misclassification of neutral variants within the cohort of patients of the German Consortium for Hereditary Breast and Ovarian Cancer. CONCLUSION We show that due to low specificities state-of-the-art in silico prediction tools are not suitable to predict pathogenicity of variants of uncertain significance in BRCA1/2. Thus, clinical consequences should never be based solely on in silico forecasts. However, our data suggests that SIFT and MutationTaster2 could be suitable to predict benignity, as both tools did not result in false negative predictions in our analysis.

Authors: Corinna Ernst, Eric Hahnen, Christoph Engel, Michael Nothnagel, Jonas Weber, Rita K. Schmutzler, Jan Hauke

Date Published: 1st Dec 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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

Olfactory dysfunction: properties of the Sniffin' Sticks Screening 12 test and associations with quality of life.
LIFE Adult

Abstract (Expand)

PURPOSE: The Sniffin' Sticks Screening 12 test is a test of olfactory performance based on pen-like odor dispensing devices. The aims of this study were to analyze the performance of this test in … a general population sample and to explore associations between olfactory dysfunction and quality of life. METHODS: A large community sample (n = 7267) completed the Sniffin' Sticks Screening 12 test and several questionnaires measuring quality of life, anxiety, dispositional optimism, social support, and satisfaction with life. RESULTS: According to the criteria recommended by the test manufacturer, 5.1% of the participants were anosmic (score </= 6), 52.4% were dysosmic (7 </= score </= 10), and 42.5% were normosmic (score >/= 11). While frequencies of correct identification differed between the 12 sticks, all sticks contributed positively to the test results. The associations between olfactory functioning and quality of life variables were negligible. In the multivariate analyses, none of the associations reached the 1% significance level. CONCLUSIONS: While studies with patients in otorhinolaryngological clinics often report substantial detriments to their quality of life in relation to olfactory dysfunction, the present epidemiological study cannot confirm this association for the general population.

Authors: A. Hinz, T. Luck, S. G. Riedel-Heller, P. Y. Herzberg, C. Rolffs, K. Wirkner, C. Engel

Date Published: 21st Nov 2018

Publication Type: Not specified

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Background Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective …e studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers. Methods Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort. Results For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and \geq4 FTPs, respectively, Ptrend \textless .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort Ptrend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98). Conclusions These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers.

Authors: Mary Beth Terry, Yuyan Liao, Karin Kast, Antonis C. Antoniou, Jasmine A. McDonald, Thea M. Mooij, Christoph Engel, Catherine Nogues, Bruno Buecher, Véronique Mari, Jessica Moretta-Serra, Laurence Gladieff, Elisabeth Luporsi, Daniel Barrowdale, Debra Frost, Alex Henderson, Carole Brewer, D. Gareth Evans, Diana Eccles, Jackie Cook, Kai-Ren Ong, Louise Izatt, Munaza Ahmed, Patrick J. Morrison, Charlotte J. Dommering, Jan C. Oosterwijk, Margreet G. E. M. Ausems, Mieke Kriege, Saundra S. Buys, Irene L. Andrulis, Esther M. John, Mary Daly, Michael Friedlander, Sue Anne McLachlan, Ana Osorio, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Christian F. Singer, Yen Tan, Edith Olah, Marie Navratilova, Lenka Foretova, Anne-Marie Gerdes, Marie-José Roos-Blom, Brita Arver, Håkan Olsson, Rita K. Schmutzler, John L. Hopper, Flora E. van Leeuwen, David Goldgar, Roger L. Milne, Douglas F. Easton, Matti A. Rookus, Nadine Andrieu

Date Published: 1st Oct 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely … unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P \textless 5.82 \times 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

Authors: Lang Wu, Wei Shi, Jirong Long, Xingyi Guo, Kyriaki Michailidou, Jonathan Beesley, Manjeet K. Bolla, Xiao-Ou Shu, Yingchang Lu, Qiuyin Cai, Fares Al-Ejeh, Esdy Rozali, Qin Wang, Joe Dennis, Bingshan Li, Chenjie Zeng, Helian Feng, Alexander Gusev, Richard T. Barfield, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Myrto Barrdahl, Caroline Baynes, Matthias W. Beckmann, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Per Broberg, Sara Y. Brucker, Barbara Burwinkel, Trinidad Caldés, Federico Canzian, Brian D. Carter, J. Esteban Castelao, Jenny Chang-Claude, Xiaoqing Chen, Ting-Yuan David Cheng, Hans Christiansen, Christine L. Clarke, Margriet Collée, Sten Cornelissen, Fergus J. Couch, David Cox, Angela Cox, Simon S. Cross, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Peter Devilee, Kimberly F. Doheny, Thilo Dörk, Isabel Dos-Santos-Silva, Martine Dumont, Miriam Dwek, Diana M. Eccles, Ursula Eilber, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, Laura Fachal, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Susan M. Gapstur, Montserrat García-Closas, Mia M. Gaudet, Maya Ghoussaini, Graham G. Giles, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Pascal Guénel, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Emily Hallberg, Ute Hamann, Patricia Harrington, Alexander Hein, Belynda Hicks, Peter Hillemanns, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Kristine Jones, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Michael J. Kerin, Elza Khusnutdinova, Veli-Matti Kosma, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Sara Lindström, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jan Lubinski, Craig Luccarini, Michael P. Lux, Robert J. MacInnis, Tom Maishman, Ivana Maleva Kostovska, Arto Mannermaa, JoAnn E. Manson, Sara Margolin, Dimitrios Mavroudis, Hanne Meijers-Heijboer, Alfons Meindl, Usha Menon, Jeffery Meyer, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Sune F. Nielsen, Børge G. Nordestgaard, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Paolo Peterlongo, Julian Peto, Dijana Plaseska-Karanfilska, Ross Prentice, Nadege Presneau, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Jane Romm, Anja Rudolph, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Rodney J. Scott, Christopher G. Scott, Sheila Seal, Mitul Shah, Martha J. Shrubsole, Ann Smeets, Melissa C. Southey, John J. Spinelli, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William Tapper, Jack A. Taylor, Mary Beth Terry, Daniel C. Tessier, Abigail Thomas, Kathrin Thöne, Rob A. E. M. Tollenaar, Diana Torres, Thérèse Truong, Michael Untch, Celine Vachon, David van den Berg, Daniel Vincent, Quinten Waisfisz, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter C. Willett, Robert Winqvist, Alicja Wolk, Lucy Xia, Xiaohong R. Yang, Argyrios Ziogas, Elad Ziv, Alison M. Dunning, Paul D. P. Pharoah, Jacques Simard, Roger L. Milne, Stacey L. Edwards, Peter Kraft, Douglas F. Easton, Georgia Chenevix-Trench, Wei Zheng

Date Published: 1st Jul 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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