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RAD51 135G–C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5’ untranslated region (UTR) of RAD51, … 135G–\textgreaterC, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G–\textgreaterC SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval CI 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G–\textgreaterC variant affects RAD51 splicing within the 5’ UTR. Thus, 135G–\textgreaterC may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

Authors: Antonis C. Antoniou, Olga M. Sinilnikova, Jacques Simard, Mélanie Léoné, Martine Dumont, Susan L. Neuhausen, Jeffery P. Struewing, Dominique Stoppa-Lyonnet, Laure Barjhoux, David J. Hughes, Isabelle Coupier, Muriel Belotti, Christine Lasset, Valérie Bonadona, Yves-Jean Bignon, Timothy R. Rebbeck, Theresa Wagner, Henry T. Lynch, Susan M. Domchek, Katherine L. Nathanson, Judy E. Garber, Jeffrey Weitzel, Steven A. Narod, Gail Tomlinson, Olufunmilayo I. Olopade, Andrew Godwin, Claudine Isaacs, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Bohdan Górski, Tomasz Byrski, Tomasz Huzarski, Susan Peock, Margaret Cook, Caroline Baynes, Alexandra Murray, Mark Rogers, Peter A. Daly, Huw Dorkins, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Amanda B. Spurdle, Xiaoqing Chen, Nicola Waddell, Nicole Cloonan, Tomas Kirchhoff, Kenneth Offit, Eitan Friedman, Bella Kaufmann, Yael Laitman, Gilli Galore, Gad Rennert, Flavio Lejbkowicz, Leon Raskin, Irene L. Andrulis, Eduard Ilyushik, Hilmi Ozcelik, Peter Devilee, Maaike P. G. Vreeswijk, Mark H. Greene, Sheila A. Prindiville, Ana Osorio, Javier Benitez, Michal Zikan, Csilla I. Szabo, Outi Kilpivaara, Heli Nevanlinna, Ute Hamann, Francine Durocher, Adalgeir Arason, Fergus J. Couch, Douglas F. Easton, Georgia Chenevix-Trench

Date Published: 1st Dec 2007

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Recorded and Reported Sleepiness: The Association Between Brain Arousal in Resting State and Subjective Daytime Sleepiness.
LIFE Adult

Abstract (Expand)

Objectives: Daytime sleepiness is a significant public health concern. Early evidence points toward the computerized VIGALL (Vigilance Algorithm Leipzig) as time-efficient tool to assess sleepiness … objectively. In the present study, we investigated the association between VIGALL variables of EEG vigilance (indicating brain arousal in resting state) and subjective daytime sleepiness in the LIFE cohort study. Additionally, we validated VIGALL against the self-rated likelihood of having fallen asleep during the conducted resting EEG and against heart periods. Methods: Participants of the primary sample LIFE 60+ (N = 1927, 60-79 years) and replication sample LIFE 40+ (N = 293, 40-56 years) completed the Epworth Sleepiness Scale (ESS). After an average interval of 3 weeks (LIFE 60+) and 65 weeks (LIFE 40+), respectively, participants underwent a single 20-minute resting EEG, analyzed using VIGALL 2.1. Results: Analyses revealed significant associations between ESS and EEG vigilance in LIFE 60+ (rho = -0.17, p = 1E-14) and LIFE 40+ (rho = -0.24, p = 2E-5). Correlations between EEG vigilance and self-rated sleep likelihood reached rho = -0.43 (p = 2E-91) in LIFE 60+ and rho = -0.50 (p = 5E-20) in LIFE 40+. Overall, strongest correlations were obtained for EEG vigilance variable "slope index." Furthermore, lower EEG vigilance was consistently associated with longer heart periods. Conclusions: The present study contributes to the validation of VIGALL. Despite the considerable interval between ESS and EEG assessment dates, the strength of ESS-VIGALL association approximates prior ESS-Multiple Sleep Latency Test results. In this light, VIGALL might constitute an economical choice for the objective assessment of daytime sleepiness in large cohort studies. The discriminative power to identify disorders of hypersomnolence, however, remains to be addressed.

Authors: P. Jawinski, J. Kittel, C. Sander, J. Huang, J. Spada, C. Ulke, K. Wirkner, T. Hensch, U. Hegerl

Date Published: 1st Jul 2017

Publication Type: Journal article

Reference intervals for leukocyte subsets in adults: Results from a population-based study using 10-color flow cytometry.
LIFE Adult

Abstract (Expand)

BACKGROUND: Reference intervals for leukocyte subsets from peripheral blood are helpful for the understanding of disease states and therapy effects. METHODS: We performed in-depth immunophenotyping for … 608 healthy German adults from the Leipzig region from 40 to 79 years by 10-color flow cytometry (FCM) to gain reference information for various leukocyte subsets including subsets of granulocytes, monocytes and lymphocytes. RESULTS: First, we derived gender- and age-specific reference intervals for males and females from 40 to 59 and from 60 to 79 years, respectively. Second, we further investigated the influence of gender and age on leukocyte counts. We found significantly higher cell counts for monocytes (P < 0.001) and NK cells (P < 0.001) in men, whereas women had higher counts for B cells (P < 0.001), Th cells (P < 0.001) and regulatory T cells (P = 0.008). Furthermore, with increasing age, a decrease in Tc cells (about 8% within 5 years) and an increase in NK cells (<4% within 5 years) were observed. CONCLUSION: In future research, it should be investigated whether these are real ageing effects that can be confirmed in longitudinal studies. Furthermore, it is important to understand if the Tc cell count drop is functionally compensated by the increase of NK cells.

Authors: S. Melzer, S. Zachariae, J. Bocsi, C. Engel, M. Loffler, A. Tarnok

Date Published: 24th Feb 2015

Publication Type: Not specified

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological …l features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. METHODS Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. RESULTS ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). CONCLUSIONS These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.

Authors: Amanda B. Spurdle, Fergus J. Couch, Michael T. Parsons, Lesley McGuffog, Daniel Barrowdale, Manjeet K. Bolla, Qin Wang, Sue Healey, Rita Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Eric Hahnen, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Steve Ellis, Debra Frost, Radka Platte, Jo Perkins, D. Gareth Evans, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Giulietta Scuvera, Siranoush Manoukian, Bernardo Bonanni, Frederique Mariette, Stefano Fortuzzi, Alessandra Viel, Barbara Pasini, Laura Papi, Liliana Varesco, Rosemary Balleine, Katherine L. Nathanson, Susan M. Domchek, Kenneth Offitt, Anna Jakubowska, Noralane Lindor, Mads Thomassen, Uffe Birk Jensen, Johanna Rantala, Åke Borg, Irene L. Andrulis, Alexander Miron, Thomas v. O. Hansen, Trinidad Caldes, Susan L. Neuhausen, Amanda E. Toland, Heli Nevanlinna, Marco Montagna, Judy Garber, Andrew K. Godwin, Ana Osorio, Rachel E. Factor, Mary B. Terry, Timothy R. Rebbeck, Beth Y. Karlan, Melissa Southey, Muhammad Usman Rashid, Nadine Tung, Paul D. P. Pharoah, Fiona M. Blows, Alison M. Dunning, Elena Provenzano, Per Hall, Kamila Czene, Marjanka K. Schmidt, Annegien Broeks, Sten Cornelissen, Senno Verhoef, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Dennis J. Slamon, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Jenny Chang-Claude, Dieter Flesch-Janys, Anja Rudolph, Petra Seibold, Kristiina Aittomäki, Taru A. Muranen, Päivi Heikkilä, Carl Blomqvist, Jonine Figueroa, Stephen J. Chanock, Louise Brinton, Jolanta Lissowska, Janet E. Olson, Vernon S. Pankratz, Esther M. John, Alice S. Whittemore, Dee W. West, Ute Hamann, Diana Torres, Hans Ulrich Ulmer, Thomas Rüdiger, Peter Devilee, Robert A. E. M. Tollenaar, Caroline Seynaeve, Christi J. van Asperen, Diana M. Eccles, William J. Tapper, Lorraine Durcan, Louise Jones, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Miriam Dwek, Ruth Swann, Anita L. Bane, Gord Glendon, Anna M. Mulligan, Graham G. Giles, Roger L. Milne, Laura Baglietto, Catriona McLean, Jane Carpenter, Christine Clarke, Rodney Scott, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, Angela Cox, Simon S. Cross, Malcolm W. R. Reed, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Thilo Dörk, Natalia Bogdanova, Tjoung-Won Park-Simon, Peter Hillemanns, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Barbara Burwinkel, Frederik Marme, Harald Surovy, Rongxi Yang, Hoda Anton-Culver, Argyrios Ziogas, Maartje J. Hooning, J. Margriet Collée, John W. M. Martens, Madeleine M. A. Tilanus-Linthorst, Hermann Brenner, Aida Karina Dieffenbach, Volke Arndt, Christa Stegmaier, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Annika Lindblom, Sara Margolin, Vijai Joseph, Mark Robson, Rohini Rau-Murthy, Anna González-Neira, José Ignacio Arias, Pilar Zamora, Javier Benítez, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Paolo Peterlongo, Daniela Zaffaroni, Monica Barile, Fabio Capra, Paolo Radice, Soo H. Teo, Douglas F. Easton, Antonis C. Antoniou, Georgia Chenevix-Trench, David E. Goldgar

Date Published: 1st Dec 2014

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term … mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9.9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1.44, 95% CI 1.14-1.83) and the presence of either LPA SNP (1.88, 1.40-2.53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0.95, 0.81-1.11 and either LPA SNP 1.10, 0.92-1.31) or cardiovascular mortality (0.99, 0.81-1.2 and 1.13, 0.90-1.40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung fur Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

Authors: S. Zewinger, M. E. Kleber, V. Tragante, R. O. McCubrey, A. F. Schmidt, K. Direk, U. Laufs, C. Werner, W. Koenig, D. Rothenbacher, U. Mons, L. P. Breitling, H. Brenner, R. T. Jennings, I. Petrakis, S. Triem, M. Klug, A. Filips, S. Blankenberg, C. Waldeyer, C. Sinning, R. B. Schnabel, K. J. Lackner, E. Vlachopoulou, O. Nygard, G. F. T. Svingen, E. R. Pedersen, G. S. Tell, J. Sinisalo, M. S. Nieminen, R. Laaksonen, S. Trompet, R. A. J. Smit, N. Sattar, J. W. Jukema, H. V. Groesdonk, G. Delgado, T. Stojakovic, A. P. Pilbrow, V. A. Cameron, A. M. Richards, R. N. Doughty, Y. Gong, R. Cooper-DeHoff, J. Johnson, M. Scholz, F. Beutner, J. Thiery, J. G. Smith, R. O. Vilmundarson, R. McPherson, A. F. R. Stewart, S. Cresci, P. A. Lenzini, J. A. Spertus, O. Olivieri, D. Girelli, N. I. Martinelli, A. Leiherer, C. H. Saely, H. Drexel, A. Mundlein, P. S. Braund, C. P. Nelson, N. J. Samani, D. Kofink, I. E. Hoefer, G. Pasterkamp, A. A. Quyyumi, Y. A. Ko, J. A. Hartiala, H. Allayee, W. H. W. Tang, S. L. Hazen, N. Eriksson, C. Held, E. Hagstrom, L. Wallentin, A. Akerblom, A. Siegbahn, I. Karp, C. Labos, L. Pilote, J. C. Engert, J. M. Brophy, G. Thanassoulis, P. Bogaty, W. Szczeklik, M. Kaczor, M. Sanak, S. S. Virani, C. M. Ballantyne, V. V. Lee, E. Boerwinkle, M. V. Holmes, B. D. Horne, A. Hingorani, F. W. Asselbergs, R. S. Patel, B. K. Kramer, H. Scharnagl, D. Fliser, W. Marz, T. Speer

Date Published: 2nd Jun 2017

Publication Type: Journal article

Relationship Between Determinants of Arterial Stiffness Assessed by Diastolic and Suprasystolic Pulse Oscillometry: Comparison of Vicorder and Vascular Explorer.
Genetical Statistics and Systems Biology, LIFE Heart

Abstract (Expand)

Pulse wave velocity (PWV) and augmentation index (AI) are independent predictors of cardiovascular health. However, the comparability of multiple oscillometric modalities currently available for their … assessment was not studied in detail. In the present study, we aimed to evaluate the relationship between indices of arterial stiffness assessed by diastolic and suprasystolic oscillometry.In total, 56 volunteers from the general population (23 males; median age 70 years [interquartile range: 65-72 years]) were recruited into observational feasibility study to evaluate the carotid-femoral/aortic PWV (cf/aoPWV), brachial-ankle PWV (baPWV), and AI assessed by 2 devices: Vicorder (VI) applying diastolic, right-sided oscillometry for the determination of all 3 indices, and Vascular explorer (VE) implementing single-point, suprasystolic brachial oscillometry (SSBO) pulse wave analysis for the assessment of cfPWV and AI. Within- and between-device correlations of measured parameters were analyzed. Furthermore, agreement of repeated measurements, intra- and inter-observer concordances were determined and compared for both devices.In VI, both baPWV and cfPWV inter-correlated well and showed good level of agreement with bilateral baPWV measured by VE (baPWV[VI]-baPWV[VE]R: overall concordance correlation coefficient [OCCC] = 0.484, mean difference = 1.94 m/s; cfPWV[VI]-baPWV[VE]R: OCCC = 0.493, mean difference = 1.0 m/s). In contrast, SSBO-derived aortic PWA (cf/aoPWA[VE]) displayed only weak correlation with cfPWV(VI) (r = 0.196; P = 0.04) and ipsilateral baPWV (cf/aoPWV[VE]R-baPWV[VE]R: r = 0.166; P = 0.08). cf/aoPWA(VE) correlated strongly with AI(VE) (right-sided: r = 0.725, P < 0.001). AI exhibited marginal between-device agreement (right-sided: OCCC = 0.298, mean difference: 6.12%). All considered parameters showed good-to-excellent repeatability giving OCCC > 0.9 for 2-point-PWV modes and right-sided AI(VE). Intra- and inter-observer concordances were similarly high except for AI yielding a trend toward better reproducibility in VE (interobserver-OCCC[VI] vs [VE] = 0.774 vs 0.844; intraobserver-OCCC[VI] vs [VE] = 0.613 vs 0.769).Both diastolic oscillometry-derived PWV modes, and AI measured either with VI or VE, are comparable and reliable alternatives for the assessment of arterial stiffness. Aortic PWV assessed by SSBO in VE is not related to the corresponding indices determined by traditional diastolic oscillometry.

Authors: A. Teren, F. Beutner, K. Wirkner, M. Loffler, M. Scholz

Date Published: 11th Mar 2016

Publication Type: Journal article

Research in Progress on Integrating Health and Environmental Data in Epidemiological Studies
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Epidemiological studies analyze and monitor the health state of a population. They typically use different methods and techniques to capture and to integrate data of interest before they can be analyzed. … As new technologies and, thus, devices are available for data capturing, such as wearables, new requirements arise for current data integration approaches. In this paper, we review current techniques and approaches as well as new trends in data capturing and the resulting requirement for its integration.

Authors: T. Kirsten, J. Bumberger, G. Ivanova, P. Dietrich, C. Engel, M. Loeffler, W. Kiess

Date Published: 2017

Publication Type: InBook

Response to the letter on 'Validating new diagnostic imaging criteria for primary progressive aphasia via anatomical likelihood estimation meta-analyses'.
LIFE Adult

Abstract

Not specified

Authors: S. Bisenius, J. Neumann, M. L. Schroeter

Date Published: 20th Jul 2016

Publication Type: Not specified

Human Diseases: dementia, aphasia

Resting-state functional magnetic resonance imaging of the subthalamic microlesion and stimulation effects in Parkinson's disease: Indications of a principal role of the brainstem.
LIFE Adult

Abstract (Expand)

During implantation of deep-brain stimulation (DBS) electrodes in the target structure, neurosurgeons and neurologists commonly observe a "microlesion effect" (MLE), which occurs well before … initiating subthalamic DBS. This phenomenon typically leads to a transitory improvement of motor symptoms of patients suffering from Parkinson's disease (PD). Mechanisms behind MLE remain poorly understood. In this work, we exploited the notion of ranking to assess spontaneous brain activity in PD patients examined by resting-state functional magnetic resonance imaging in response to penetration of DBS electrodes in the subthalamic nucleus. In particular, we employed a hypothesis-free method, eigenvector centrality (EC), to reveal motor-communication-hubs of the highest rank and their reorganization following the surgery; providing a unique opportunity to evaluate the direct impact of disrupting the PD motor circuitry in vivo without prior assumptions. Penetration of electrodes was associated with increased EC of functional connectivity in the brainstem. Changes in connectivity were quantitatively related to motor improvement, which further emphasizes the clinical importance of the functional integrity of the brainstem. Surprisingly, MLE and DBS were associated with anatomically different EC maps despite their similar clinical benefit on motor functions. The DBS solely caused an increase in connectivity of the left premotor region suggesting separate pathophysiological mechanisms of both interventions. While the DBS acts at the cortical level suggesting compensatory activation of less affected motor regions, the MLE affects more fundamental circuitry as the dysfunctional brainstem predominates in the beginning of PD. These findings invigorate the overlooked brainstem perspective in the understanding of PD and support the current trend towards its early diagnosis.

Authors: S. Holiga, K. Mueller, H. E. Moller, D. Urgosik, E. Ruzicka, M. L. Schroeter, R. Jech

Date Published: 29th Oct 2015

Publication Type: Not specified

Human Diseases: Parkinson's disease

Risk of dementia in older adults with low versus high occupation-based motivational processes: differential impact of frequency and proximity of social network.
LIFE Adult

Abstract (Expand)

OBJECTIVES: This study investigates the impact of occupation-based motivational processes and social network variables on the incidence of dementia over 8 years. METHOD: Data were derived from the … Leipzig Longitudinal Study of the Aged (LEILA75+), a population-based longitudinal study of individuals aged 75 years and older (n=1692 at baseline). Motivational processes were estimated based on the main occupation using the Occupational Information Network database. RESULTS: In a Cox proportional hazard model, motivational processes were not associated with the risk of dementia (hazard ratio [HR]: 0.93, 95% confidence interval [CI]: 0.74-1.16). Individuals with a higher frequency of social contact at baseline had a significantly lower risk of dementia (HR: 0.96, 95% CI: 0.91-0.99), while proximity of social contacts was not linked to the risk of dementia (HR: 1.03, 95% CI: 0.98-1.08). In individuals with low indices of motivational processes, the frequency of social contacts was associated with a lower risk of dementia (HR: 0.94, 95% CI: 0.88-1.00). On the other hand, proximity of social contacts was linked to a higher risk of dementia in individuals with high indices of motivational processes (HR: 1.09, 95% CI: 1.01-1.19). DISCUSSION: Results indicate that the frequency and proximity of social contacts have a differential impact on the risk of dementia according to lower or higher indices of motivational processes, while the impact of motivational processes on risk of dementia could not be confirmed. Future studies should carefully disentangle different aspects of social interactions and their association with motivational processes.

Authors: S. Fankhauser, S. Forstmeier, A. Maercker, M. Luppa, T. Luck, S. G. Riedel-Heller

Date Published: 29th Nov 2014

Publication Type: Not specified

Human Diseases: dementia

Risk-reducing salpingo-oophorectomy, natural menopause, and breast cancer risk: an international prospective cohort of BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The effect of risk-reducing salpingo-oophorectomy (RRSO) on breast cancer risk for BRCA1 and BRCA2 mutation carriers is uncertain. Retrospective analyses have suggested a protective effect …t but may be substantially biased. Prospective studies have had limited power, particularly for BRCA2 mutation carriers. Further, previous studies have not considered the effect of RRSO in the context of natural menopause. METHODS A multi-centre prospective cohort of 2272 BRCA1 and 1605 BRCA2 mutation carriers was followed for a mean of 5.4 and 4.9 years, respectively; 426 women developed incident breast cancer. RRSO was modelled as a time-dependent covariate in Cox regression, and its effect assessed in premenopausal and postmenopausal women. RESULTS There was no association between RRSO and breast cancer for BRCA1 (HR = 1.23; 95% CI 0.94-1.61) or BRCA2 (HR = 0.88; 95% CI 0.62-1.24) mutation carriers. For BRCA2 mutation carriers, HRs were 0.68 (95% CI 0.40-1.15) and 1.07 (95% CI 0.69-1.64) for RRSO carried out before or after age 45 years, respectively. The HR for BRCA2 mutation carriers decreased with increasing time since RRSO (HR = 0.51; 95% CI 0.26-0.99 for 5 years or longer after RRSO). Estimates for premenopausal women were similar. CONCLUSION We found no evidence that RRSO reduces breast cancer risk for BRCA1 mutation carriers. A potentially beneficial effect for BRCA2 mutation carriers was observed, particularly after 5 years following RRSO. These results may inform counselling and management of carriers with respect to RRSO.

Authors: Nasim Mavaddat, Antonis C. Antoniou, Thea M. Mooij, Maartje J. Hooning, Bernadette A. Heemskerk-Gerritsen, Catherine Noguès, Marion Gauthier-Villars, Olivier Caron, Paul Gesta, Pascal Pujol, Alain Lortholary, Daniel Barrowdale, Debra Frost, D. Gareth Evans, Louise Izatt, Julian Adlard, Ros Eeles, Carole Brewer, Marc Tischkowitz, Alex Henderson, Jackie Cook, Diana Eccles, Klaartje van Engelen, Marian J. E. Mourits, Margreet G. E. M. Ausems, Linetta B. Koppert, John L. Hopper, Esther M. John, Wendy K. Chung, Irene L. Andrulis, Mary B. Daly, Saundra S. Buys, Javier Benitez, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Christian F. Singer, Yen Tan, Edith Olah, Marie Navratilova, Lenka Foretova, Anne-Marie Gerdes, Marie-José Roos-Blom, Flora E. van Leeuwen, Brita Arver, Håkan Olsson, Rita K. Schmutzler, Christoph Engel, Karin Kast, Kelly-Anne Phillips, Mary Beth Terry, Roger L. Milne, David E. Goldgar, Matti A. Rookus, Nadine Andrieu, Douglas F. Easton

Date Published: 1st Dec 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Importance The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives To estimate age-specific risks of breast, ovarian, and contralateral …ral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for \geq2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P\textless.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P\textless.001). Conclusions and Relevance These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

Authors: Karoline B. Kuchenbaecker, John L. Hopper, Daniel R. Barnes, Kelly-Anne Phillips, Thea M. Mooij, Marie-José Roos-Blom, Sarah Jervis, Flora E. van Leeuwen, Roger L. Milne, Nadine Andrieu, David E. Goldgar, Mary Beth Terry, Matti A. Rookus, Douglas F. Easton, Antonis C. Antoniou, Lesley McGuffog, D. Gareth Evans, Daniel Barrowdale, Debra Frost, Julian Adlard, Kai-Ren Ong, Louise Izatt, Marc Tischkowitz, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Steve Ellis, Catherine Nogues, Christine Lasset, Dominique Stoppa-Lyonnet, Jean-Pierre Fricker, Laurence Faivre, Pascaline Berthet, Maartje J. Hooning, Lizet E. van der Kolk, Carolien M. Kets, Muriel A. Adank, Esther M. John, Wendy K. Chung, Irene L. Andrulis, Melissa Southey, Mary B. Daly, Saundra S. Buys, Ana Osorio, Christoph Engel, Karin Kast, Rita K. Schmutzler, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Michael L. Friedlander, Sue-Anne McLachlan, Eva Machackova, Lenka Foretova, Yen Y. Tan, Christian F. Singer, Edith Olah, Anne-Marie Gerdes, Brita Arver, Håkan Olsson

Date Published: 20th Jun 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Risks of less common cancers in proven mutation carriers with lynch syndrome.
GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Abstract (Expand)

PURPOSE: Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was … to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. PATIENTS AND METHODS: Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. RESULTS: The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. CONCLUSION: The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome.

Authors: C. Engel, M. Loeffler, V. Steinke, N. Rahner, E. Holinski-Feder, W. Dietmaier, H. K. Schackert, H. Goergens, M. von Knebel Doeberitz, T. O. Goecke, W. Schmiegel, R. Buettner, G. Moeslein, T. G. Letteboer, E. Gomez Garcia, F. J. Hes, N. Hoogerbrugge, F. H. Menko, T. A. van Os, R. H. Sijmons, A. Wagner, I. Kluijt, P. Propping, H. F. Vasen

Date Published: 10th Dec 2012

Publication Type: Not specified

Human Diseases: colon cancer

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