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265 Publications visible to you, out of a total of 265
A BRCA1 promoter variant (rs11655505) and breast cancer risk
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND A study of Chinese women recently suggested that the minor allele of rs11655505 in the BRCA1 promoter (c.-2265C–\textgreaterT) increases promoter activity and has a protective effect on …n breast cancer risk. METHODS We genotyped rs11655505 in 2912 female breast cancer cases and 2783 unaffected female controls from four Caucasian breast cancer studies. RESULTS No evidence for an association between rs11655505 and breast cancer risk was found. CONCLUSIONS Our study failed to confirm a role of rs11655505 in breast cancer risk. Larger studies are necessary to determine if there is a weak association between this SNP and breast cancer risk.

Authors: Paolo Verderio, Sara Pizzamiglio, Melissa C. Southey, Amanda B. Spurdle, John L. Hopper, Xiaoqing Chen, Jonathan Beesley, Rita K. Schmutzler, Christoph Engel, Barbara Burwinkel, Peter Bugert, Filomena Ficarazzi, Siranoush Manoukian, Monica Barile, Barbara Wappenschmidt, Georgia Chenevix-Trench, Paolo Radice, Paolo Peterlongo

Date Published: 22nd Apr 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

A breast cancer risk haplotype in the caspase-8 gene
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Recent large-scale studies have been successful in identifying common, low-penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has … been confirmed to be associated with breast cancer risk, although the functional effect of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP). We used a staged study design based on 3,200 breast cancer and 3,324 control subjects from the United Kingdom, Utah, and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a four-SNP haplotype that was significantly associated with breast cancer and that was superior to any other single or multi-locus combination (P=8.0 x 10(-5)), with a per allele odds ratio and 95% confidence interval of 1.30 (1.12-1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate, q=0.044). As expected, this haplotype includes the D302H locus. Multicenter analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for resequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer.

Authors: Neil Duncan Shephard, Ryan Abo, Sushila Harkisandas Rigas, Bernd Frank, Wei-Yu Lin, Ian Wallace Brock, Adam Shippen, Sabapathy Prakash Balasubramanian, Malcolm Walter Ronald Reed, Claus Rainer Bartram, Alfons Meindl, Rita Katharina Schmutzler, Christoph Engel, Barbara Burwinkel, Lisa Anne Cannon-Albright, Kristina Allen-Brady, Nicola Jane Camp, Angela Cox

Date Published: 24th Mar 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The relevance of many BRCA2 variants of uncertain significance (VUS) to breast cancer has not been determined due to limited genetic information from families carrying these alterations. Here, we … classified six new variants as pathogenic or nonpathogenic by analysis of genetic information from families carrying 64 individual BRCA2 DNA binding domain (DBD) missense mutations using a multifactorial likelihood model of cancer causality. Next, we evaluated the use of a homology-directed DNA break repair (HDR) functional assay as a method for inferring the clinical relevance of VUS in the DBD of BRCA2 using 18 established nonpathogenic missense variants and all 13 established pathogenic missense mutations from the BRCA2 DBD. Compared with the known status of these variants based on the multifactorial likelihood model, the sensitivity of the HDR assay for pathogenic mutations was estimated at 100% [95% confidence interval (CI): 75.3%-100%] and specificity was estimated at 100% (95% CI: 81.5%-100%). A statistical classifier for predicting the probability of pathogenicity of BRCA2 DBD variants was developed using these functional results. When applied to 33 additional VUS, the classifier identified eight with 99% or more probability of nonpathogenicity and 18 with 99% or more probability of pathogenicity. Thus, in the absence of genetic evidence, a cell-based HDR assay can provide a probability of pathogenicity for all VUS in the BRCA2 DBD, suggesting that the assay can be used in combination with other information to determine the cancer relevance of BRCA2 VUS.

Authors: Lucia Guidugli, Vernon S. Pankratz, Namit Singh, James Thompson, Catherine A. Erding, Christoph Engel, Rita Schmutzler, Susan Domchek, Katherine Nathanson, Paolo Radice, Christian Singer, Patricia N. Tonin, Noralane M. Lindor, David E. Goldgar, Fergus J. Couch

Date Published: 2nd Jan 2013

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer.
GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Abstract (Expand)

OBJECTIVE: Microsatellite instability (MSI) is detected in approximately 15% of all colorectal cancers (CRC) and virtually in all cases with Lynch syndrome. The MSI phenotype is caused by dysfunctional … mismatch repair (MMR) and leads to accumulation of DNA replication errors. Sporadic MSI CRC often harbours BRAF(V600E); however, no consistent data exist regarding targeted treatment approaches in BRAF(wt) MSI CRC. DESIGN: Mutations and quantitative MSI were analysed by deep sequencing in 196 formalin fixed paraffin embedded (FFPE) specimens comprising Lynch and Lynch-like CRCs from the German Hereditary Nonpolyposis Colorectal Cancer registry. Functional relevance of recurrent ERBB2/HER2 mutations was investigated in CRC cell lines using reversible and irreversible HER-targeting inhibitors, EGFR-directed antibody cetuximab, HER2-directed antibody trastuzumab and siRNA-mediated ERBB2/HER2 knockdown. RESULTS: Quantification of nucleotide loss in non-coding mononucleotide repeats distinguished microsatellite status with very high accuracy (area under curve=0.9998) and demonstrated progressive losses with deeper invasion of MMR-deficient colorectal neoplasms (p=0.008). Characterisation of BRAF(wt) MSI CRC revealed hot-spot mutations in well-known oncogenic drivers, including KRAS (38.7%), PIK3CA (36.5%), and ERBB2 (15.0%). L755S and V842I substitutions in ERBB2 were highly recurrent. Functional analyses in ERBB2-mutated MSI CRC cell lines revealed a differential response to HER-targeting compounds and superiority of irreversible pan-HER inhibitors. CONCLUSIONS: We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens. We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC.

Authors: M. Kloth, V. Ruesseler, C. Engel, K. Koenig, M. Peifer, E. Mariotti, H. Kuenstlinger, A. Florin, U. Rommerscheidt-Fuss, U. Koitzsch, C. Wodtke, F. Ueckeroth, S. Holzapfel, S. Aretz, P. Propping, M. Loeffler, S. Merkelbach-Bruse, M. Odenthal, N. Friedrichs, L. C. Heukamp, T. Zander, R. Buettner

Date Published: 24th May 2015

Publication Type: Not specified

Human Diseases: colorectal cancer

Acute renal failure in patients with severe sepsis and septic shock–a significant independent risk factor for mortality: results from the German Prevalence Study
SepNet - German Competence Network Sepsis

Abstract (Expand)

BACKGROUND Sound data about the prevalence of acute renal failure (ARF) among patients with severe sepsis and septic shock are lacking. Further, it is not known whether ARF is an independent risk factor …r for mortality in septic patients or merely an indicator of disease severity. METHODS A prospective cross-sectional one-day prevalence study was carried out in a representative sample of German ICUs, divided into five strata (\textless 200 beds; 201-400 beds; 401-600 beds; \textgreater 600 beds; university hospitals). 3877 patients were screened of whom 415 had severe sepsis and septic shock. RESULTS Fourteen patients (3.4%) had chronic dialysis-dependent RF and were excluded from analysis. Of the remaining 401 patients, 166 (41.4%) had ARF, as defined by a rise in creatinine above twice the upper limit of normal and/or a drop in urine output to \textless 0.5 ml/kg bodyweight. Median APACHE II score was 22 in patients with ARF and 16 in patients without ARF (p\textless 0.0001). Patients with severe sepsis/septic shock had an overall hospital mortality of 55.2%. Hospital mortality in patients with ARF was 67.3% and without ARF 42.8% (p\textless 0.0001). After adjustment for APACHE II score and age, ARF remained a significant independent risk factor for death [odds ratio (OR) 2.11, 95% confidence interval (CI) 1.27-3.52]. Mortality in septic patients was not associated with pre-existing, non-dialysis-dependent chronic kidney disease, whereas in dialysis-dependent patients with sepsis mortality increased to 86%. CONCLUSION In this representative survey in patients with severe sepsis/septic shock, prevalence of ARF is high with 41.4%. ARF represents a significant independent risk factor for mortality in these patients.

Authors: Michael Oppert, Christoph Engel, Frank-Martin Brunkhorst, Holger Bogatsch, Konrad Reinhart, Ulrich Frei, Kai-Uwe Eckardt, Markus Loeffler, Stefan John

Date Published: 15th Oct 2007

Publication Type: Journal article

Human Diseases: disease by infectious agent

Adipose triglyceride lipase acts on neutrophil lipid droplets to regulate substrate availability for lipid mediator synthesis.
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

In humans, mutations in ATGL lead to TG accumulation in LDs of most tissues and cells, including peripheral blood leukocytes. This pathologic condition is called Jordans' anomaly, in which functional … consequences have not been investigated. In the present study, we tested the hypothesis that ATGL plays a role in leukocyte LD metabolism and immune cell function. Similar to humans with loss-of-function mutations in ATGL, we found that global and myeloid-specific Atgl(-/-) mice exhibit Jordans' anomaly with increased abundance of intracellular TG-rich LDs in neutrophil granulocytes. In a model of inflammatory peritonitis, lipid accumulation was also observed in monocytes and macrophages but not in eosinophils or lymphocytes. Neutrophils from Atgl(-/-) mice showed enhanced immune responses in vitro, which were more prominent in cells from global compared with myeloid-specific Atgl(-/-) mice. Mechanistically, ATGL(-/-) as well as pharmacological inhibition of ATGL led to an impaired release of lipid mediators from neutrophils. These findings demonstrate that the release of lipid mediators is dependent on the liberation of precursor molecules from the TG-rich pool of LDs by ATGL. Our data provide mechanistic insights into Jordans' anomaly in neutrophils and suggest that ATGL is a potent regulator of immune cell function and inflammatory diseases.

Authors: S. Schlager, M. Goeritzer, K. Jandl, R. Frei, N. Vujic, D. Kolb, H. Strohmaier, J. Dorow, T. O. Eichmann, A. Rosenberger, A. Wolfler, A. Lass, E. E. Kershaw, U. Ceglarek, A. Dichlberger, A. Heinemann, D. Kratky

Date Published: 26th Jun 2015

Publication Type: Not specified

Advance directives and power of attorney for health care in the oldest-old - results of the AgeQualiDe study.
LIFE Adult

Abstract (Expand)

BACKGROUND: Completion of advance directives (ADs) and power of attorney (POA) documents may protect a person's autonomy in future health care situations when the individual lacks decisional capacity. … As such situations become naturally much more common in old age, we specifically aimed at providing information on (i) the frequency of ADs/POA in oldest-old individuals and (ii) factors associated with having completed ADs/POA. METHODS: We analyzed data of oldest-old primary care patients (85+ years; including community-dwelling and institutionalized individuals) within the German AgeQualiDe study. Patients were initially recruited via their general practitioners (GPs). We calculated frequencies of ADs and POA for health care with 95% confidence intervals (CI) and used multivariable logistic regression analysis to evaluate the association between having ADs and POA and participants' socio-demographic, cognitive, functional, and health-related characteristics. RESULTS: Among 868 GP patients participating in AgeQualiDe (response = 90.9%), n = 161 had dementia and n = 3 were too exhausted/ill to answer the questions. Out of the remaining 704 (81.1%) dementia-free patients (mean age = 88.7 years; SD = 3.0), 69.0% (95%-CI = 65.6-72.4) stated to having ADs and 64.6% (95%-CI = 61.1-68.2) to having a POA for health care. Individual characteristics did not explain much of the variability of the presence/absence of ADs and POA (regression models: Nagelkerke's R(2) = 0.034/0.051). The most frequently stated reasons for not having ADs were that the older adults trust their relatives or physicians to make the right decisions for them when necessary (stated by 59.4% and 44.8% of those without ADs). Among the older adults with ADs, the majority had received assistance in its preparation (79.0%), most frequently from their children/grandchildren (38.3%). Children/grandchildren were also the most frequently stated group of designated persons (76.7%) for those with a POA for health care. CONCLUSIONS: Our findings suggest a high dissemination of ADs and POA for health care in the oldest-old in Germany. Some adults without ADs/POA perhaps would have completed advance care documents, if they had had received more information and support. When planning programs to offer advanced care planning to the oldest old, it might be helpful to respond to these specific needs, and also to be sensitive to attitudinal differences in this target group.

Authors: T. Luck, F. S. Rodriguez, B. Wiese, C. van der Leeden, K. Heser, H. Bickel, J. In der Schmitten, H. H. Koenig, S. Weyerer, S. Mamone, T. Mallon, M. Wagner, D. Weeg, A. Fuchs, C. Brettschneider, J. Werle, M. Scherer, W. Maier, S. G. Riedel-Heller

Date Published: 13th Apr 2017

Publication Type: Journal article

[Adverse drug reactions in elderly people : First data from the Leipzig Research Center for Civilization Diseases (LIFE)].
LIFE Adult

Abstract (Expand)

BACKGROUND: Few data exist on adverse drug reactions (ADR) in elderly people. In this group, pharmacotherapy represents a challenge with regard to comorbidities, drug interactions and compliance. … OBJECTIVE: The aim of this article is to highlight the characteristics of ADR in elderly patients. METHODS: In addition to a literature review we present the first data from the Leipzig Research Center for Civilization Diseases (LIFE). Between 2011 and 2015 a total of 9537 subjects aged 40-79 years were randomly included in this population-based, age and sex standardized investigation in the inhabitants of Leipzig, Germany and special emphasis was placed on allergies including questions with regard to ADR. RESULTS: Of the 9537 subjects, data on allergies were available from 8979 subjects. Female gender, comorbidities and the use of multiple drugs were significantly associated with an increased risk of ADR. Women also reported ADR significantly more frequently than men. Of the subjects 22% reported suffering from some form of ADR as a result of medications, while in 2.3% this reaction had occurred within the previous 12 months. Less than 15% of LIFE patients with ADR were in possession of a document giving details of the ADR. DISCUSSION: The occurrence of ADR significantly contributes to morbidity in elderly patients. For prevention of ADR knowledge of patient-related factors, underlying diseases, drug characteristics and drug interactions are necessary.

Authors: R. Treudler, F. Walther, P. Ahnert, J. C. Simon

Date Published: 23rd Nov 2016

Publication Type: Journal article

Age- and gender-specific norms for the German version of the Three-Factor Eating-Questionnaire (TFEQ).
LIFE Adult

Abstract (Expand)

The 'Fragebogen zum Essverhalten' (FEV) is the German version of the Three-factor-Eating-Questionnaire (TFEQ). This questionnaire covers three domains of eating behaviour ('cognitive … restraint', 'disinhibition' and 'hunger') as well as common problems (e.g. craving for sweets). So far, there is a lack of normative data of the FEV especially for the middle-aged and older population. Aim of this study therefore was to provide age- and gender-specific norms of the FEV for the general population aged 40-79 years. We studied 3144 participants of the ongoing large community-based Leipzig Research Center for Civilization Diseases (LIFE) Health Care Study. We provided age- (four age groups: 40-49, 50-59, 60-69, and 70-79 years) and gender-specific percentile ranks and T-scores for the three domains of the FEV as well as age- and gender-specific frequencies of the common problems in eating behaviour. Females scored significantly higher than males in all three domains of the FEV (p < 0.001). Older individuals showed significantly higher mean scores than the younger ones in the domain of cognitive restraint, but lower mean scores in disinhibition and hunger (p < 0.001). 45.1% of the males and 69.9% of the females reported specific problems in eating. The main problem in both genders was craving for sweets (38.6%). Eating in response to stress was mostly reported in younger individuals. The present study offers current normative data for the FEV in the middle-aged and older general population that can be applied in clinical and non-clinical settings. Information on eating behaviour can be helpful in understanding body weight modulation, and thus, may help to improve interventive and preventive programmes for overweight, obesity, and eating disorders.

Authors: A. Loffler, T. Luck, F. S. Then, M. Luppa, C. Sikorski, P. Kovacs, A. Tonjes, Y. Bottcher, J. Breitfeld, A. Horstmann, M. Loffler, C. Engel, J. Thiery, M. Stumvoll, S. G. Riedel-Heller

Date Published: 19th Apr 2015

Publication Type: Not specified

Human Diseases: obesity, eating disorder

Age-dependency of cardiac morphology and function: results of the LIFE-Adult-Study – analysis of the echocardiographic substudy
LIFE Adult

Abstract (Expand)

In the NORRE study (EHJCVI (2014) 15, 680 – 690) normal values determined by echocardiography were published in healthy subjects (n = 734) with mean age of 46+13 years (range: 20 – 78). Left ventricular … (LV)-volumes showed good correlations to the participants' (pts') age. LV-volumes were decreased and LV ejection fraction (EF) was increased according to the increase of the pts' age. A significant correlation between age and LV-mass was only found in women. Left atrial (LA)-volumes did not significantly change with age. Parameters of diastolic function showed a strong age-dependency (decrease of E/A-ratio; increase of E/E'-ratio). In the present LIFE-Adult analysis echocardiographic parameters were compared to the NORRE data. In 773 pts (326 males and 447 females; median age: 51 years), standardised transthoracic echocardiography was performed according to the national and international recommendations. The following parameters were analysed: LV- and LA-volume analyses by M-Mode measurements and 2D-LV planimetry, maximum E-and A-velocity, E/A-ratio and E/E'-ratio. The cohort was divided in age related subcohorts between 20 – 40, 41 – 50 and 51 – 60 years. Mean LV-diameter was 54 ± 5 mm (males) and 49 ± 4 mm (females). There was no age-dependency in males, but a tendency of LV-diameter increase in females. Mean LA diameter was 39 ± 4 mm in males and 35 ± 4 mm in females. Mean LA-diameter-index was 20 ± 2 mm/m2 (males) and 20 ± 3 mm/m2 (females) showing Age-dependency of an increasing LA-diameter in males and females. LV mass-index was 100 ± 20 g/m2 (males) and 83 ± 19 g/m2 (females) showing a tendency of increasing LV mass-index with age in males and females. Subsequently, septal and posterior wall thickness slightly increases with age. No differences of LVEF with increase of the pts' age could be observed. E/A-ratio was decreased and E/E'-ratio was increased with increase of the pts' age. The analysis of the echocardiographic parameters of the LIFE-Adult trial showed differences of the age-dependency in comparison to the NORRE data.

Authors: S. Stöbe, A. Hagendorff, S. Zeynalova, S. Tautenhahn, K. Wirkner, G. Farese, D. Jurisch, D. Pfeiffer, M. Loeffler

Date Published: 18th Aug 2016

Publication Type: Journal article

Age, ocular magnification, and circumpapillary retinal nerve fiber layer thickness.
LIFE Adult

Abstract (Expand)

Optical coherence tomography (OCT) manufacturers graphically present circumpapillary retinal nerve fiber layer thickness (cpRNFLT) together with normative limits to support clinicians in diagnosing … ophthalmic diseases. The impact of age on cpRNFLT is typically implemented by linear models. cpRNFLT is strongly location-specific, whereas previously published norms are typically restricted to coarse sectors and based on small populations. Furthermore, OCT devices neglect impacts of lens or eye size on the diameter of the cpRNFLT scan circle so that the diameter substantially varies over different eyes. We investigate the impact of age and scan diameter reported by Spectralis spectral-domain OCT on cpRNFLT in 5646 subjects with healthy eyes. We provide cpRNFLT by age and diameter at 768 angular locations. Age/diameter were significantly related to cpRNFLT on 89%/92% of the circle, respectively (pointwise linear regression), and to shifts in cpRNFLT peak locations. For subjects from age 42.1 onward but not below, increasing age significantly decreased scan diameter (r=-0.28, p<0.001), which suggests that pathological cpRNFLT thinning over time may be underestimated in elderly compared to younger subjects, as scan diameter decrease correlated with cpRNFLT increase. Our detailed numerical results may help to generate various correction models to improve diagnosing and monitoring optic neuropathies.

Authors: M. Wang, T. Elze, D. Li, N. Baniasadi, K. Wirkner, T. Kirsten, J. Thiery, M. Loeffler, C. Engel, F. G. Rauscher

Date Published: 25th Dec 2017

Publication Type: Journal article

Alcohol consumption, cigarette smoking, and risk of breast cancer for BRCA1 and BRCA2 mutation carriers: results from The BRCA1 and BRCA2 Cohort Consortium
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Tobacco smoking and alcohol consumption have been intensively studied in the general population to assess their effects on the risk of breast cancer (BC), but very few studies have examined …d these effects in BRCA1 and BRCA2 mutation carriers. Given the high BC risk for mutation carriers and the importance of BRCA1 and BRCA2 in DNA repair, better evidence on the associations of these lifestyle factors with BC risk is essential. METHODS Using a large international pooled cohort of BRCA1 and BRCA2 mutation carriers, we conducted retrospective (5,707 BRCA1 mutation carriers; 3,525 BRCA2 mutation carriers) and prospective (2,276 BRCA1 mutation carriers; 1,610 BRCA2 mutation carriers) analyses of alcohol and tobacco consumption using Cox proportional hazards models. RESULTS For both BRCA1 and BRCA2 mutation carriers, none of the smoking-related variables was associated with BC risk, except smoking for more than five years before a first full-term pregnancy (FFTP) when compared to parous women who never smoked. For BRCA1 mutation carriers, the HR from retrospective analysis (HRR) was 1.19 (95%CI:1.02,1.39) and the HR from prospective analysis (HRP) was 1.36 (95%CI:0.99,1.87). For BRCA2 mutation carriers, smoking for more than five years before a FFTP showed an association of a similar magnitude, but the confidence limits were wider (HRR=1.25,95%CI:1.01,1.55 and HRP=1.30,95%CI:0.83,2.01). For both carrier groups, alcohol consumption was not associated with BC risk. CONCLUSIONS The finding that smoking during the pre-reproductive years increases BC risk for mutation carriers warrants further investigation. IMPACT This is the largest prospective study of BRCA mutation carriers to assess these important risk factors.

Authors: Hongyan Li, Mary Beth Terry, Antonis C. Antoniou, Kelly-Anne Phillips, Karin Kast, Thea M. Mooij, Christoph Engel, Catherine Noguès, Dominique Stoppa-Lyonnet, Christine Lasset, Pascaline Berthet, Veronique Mari, Olivier Caron, Daniel Barrowdale, Debra Frost, Carole Brewer, D. Gareth Evans, Louise Izatt, Lucy Side, Lisa Walker, Marc Tischkowitz, Mark T. Rogers, Mary E. Porteous, Hanne E. J. Meijers-Heijboer, Johan Jp Gille, Marinus J. Blok, Nicoline Hoogerbrugge, Mary B. Daly, Irene L. Andrulis, Saundra S. Buys, Esther M. John, Sue-Anne McLachlan, Michael Friedlander, Yen Y. Tan, Ana Osorio, Trinidad Caldes, Anna Jakubowska, Jacques Simard, Christian F. Singer, Edith Olah, Marie Navratilova, Lenka Foretova, Anne-Marie Gerdes, Marie-José Roos-Blom, Brita Arver, Håkan Olsson, Rita K. Schmutzler, John L. Hopper, Roger L. Milne, Douglas F. Easton, Flora E. van Leeuwen, Matti A. Rookus, Nadine Andrieu, David E. Goldgar

Date Published: 5th Feb 2020

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Alcohol consumption is positively associated with fasting serum ghrelin in non-dependent adults: Results from the population-based LIFE-Adult-Study.
LIFE Adult

Abstract (Expand)

BACKGROUND: Animal experiments and studies in alcohol dependent patients indicate that ghrelin signaling in the brain is causally involved in the regulation of alcohol reward and intake. Increasing … ghrelin levels enhances alcohol craving and intake, blocking ghrelin receptors abolishes these effects. If ghrelin is also involved in non-dependent alcohol consumption in humans, though, remains unknown. The aim was therefore to investigate the relationship between ghrelin serum levels and alcohol consumption in a large population-based sample. METHODS: Total ghrelin was determined after an overnight fast in 1666 subjects participating in a population-based cross-sectional study ('LIFE') including 10,000 adults. 1521 subjects were included in this analysis. Alcohol consumption was assessed using a food frequency questionnaire (FFQ). Multiple linear regression analyses and extreme group comparisons testing for statistical differences of alcohol consumption between the highest and lowest quartile according to ghrelin levels were performed. RESULTS: Alcohol consumption was positively associated with serum ghrelin; total sample: beta = 0.003, p = 0.002; men: beta = 0.005, p = 0.023; women: beta = 0.002, p = 0.007, adjusted for age, BMI and smoking status. Mean alcohol consumption in men/women belonging to the highest quartile of serum ghrelin levels (men: 21.5 (21.1) g/day; women: 7.5 (11.4) g/day) was considerably higher than in those belonging to the lowest quartile (men: 16.5 (19.3) g/day p < 0.002; women: 4.59 (10.7) g/day p = 0.0001). CONCLUSION: This is the first study showing that alcohol consumption is positively associated with serum ghrelin in a population-based sample. The study provides an initial indication that ghrelin is also involved in the regulation of alcohol consumption in non-dependent subjects.

Authors: D. A. Wittekind, J. Kratzsch, R. Mergl, C. Enzenbach, A. V. Witte, A. Villringer, M. Kluge

Date Published: 22nd Jul 2018

Publication Type: Not specified

Human Diseases: alcohol dependence

A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed … with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 \times 10^-^9 to P(trend) = 3.9 \times 10^-^7), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 \times 10^-^7) to P(trend) = 8 \times 10^-^5; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 \times 10^-^7

Authors: Antonis C. Antoniou, Xianshu Wang, Zachary S. Fredericksen, Lesley McGuffog, Robert Tarrell, Olga M. Sinilnikova, Sue Healey, Jonathan Morrison, Christiana Kartsonaki, Timothy Lesnick, Maya Ghoussaini, Daniel Barrowdale, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Diana Eccles, D. Gareth Evans, Ros Eeles, Louise Izatt, Carol Chu, Fiona Douglas, Joan Paterson, Dominique Stoppa-Lyonnet, Claude Houdayer, Sylvie Mazoyer, Sophie Giraud, Christine Lasset, Audrey Remenieras, Olivier Caron, Agnès Hardouin, Pascaline Berthet, Frans B. L. Hogervorst, Matti A. Rookus, Agnes Jager, Ans van den Ouweland, Nicoline Hoogerbrugge, Rob B. van der Luijt, Hanne Meijers-Heijboer, Encarna B. Gómez García, Peter Devilee, Maaike P. G. Vreeswijk, Jan Lubinski, Anna Jakubowska, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Bohdan Górski, Cezary Cybulski, Amanda B. Spurdle, Helene Holland, David E. Goldgar, Esther M. John, John L. Hopper, Melissa Southey, Saundra S. Buys, Mary B. Daly, Mary-Beth Terry, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Sabine Preisler-Adams, Norbert Arnold, Dieter Niederacher, Christian Sutter, Susan M. Domchek, Katherine L. Nathanson, Timothy Rebbeck, Joanne L. Blum, Marion Piedmonte, Gustavo C. Rodriguez, Katie Wakeley, John F. Boggess, Jack Basil, Stephanie V. Blank, Eitan Friedman, Bella Kaufman, Yael Laitman, Roni Milgrom, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Tomas Kirchhoff, Joseph Vijai, Mia M. Gaudet, David Altshuler, Candace Guiducci, Niklas Loman, Katja Harbst, Johanna Rantala, Hans Ehrencrona, Anne-Marie Gerdes, Mads Thomassen, Lone Sunde, Paolo Peterlongo, Siranoush Manoukian, Bernardo Bonanni, Alessandra Viel, Paolo Radice, Trinidad Caldes, Miguel de La Hoya, Christian F. Singer, Anneliese Fink-Retter, Mark H. Greene, Phuong L. Mai, Jennifer T. Loud, Lucia Guidugli, Noralane M. Lindor, Thomas v. O. Hansen, Finn C. Nielsen, Ignacio Blanco, Conxi Lazaro, Judy Garber, Susan J. Ramus, Simon A. Gayther, Catherine Phelan, Stephen Narod, Csilla I. Szabo, Javier Benitez, Ana Osorio, Heli Nevanlinna, Tuomas Heikkinen, Maria A. Caligo, Mary S. Beattie, Ute Hamann, Andrew K. Godwin, Marco Montagna, Cinzia Casella, Susan L. Neuhausen, Beth Y. Karlan, Nadine Tung, Amanda E. Toland, Jeffrey Weitzel, Olofunmilayo Olopade, Jacques Simard, Penny Soucy, Wendy S. Rubinstein, Adalgeir Arason, Gad Rennert, Nicholas G. Martin, Grant W. Montgomery, Jenny Chang-Claude, Dieter Flesch-Janys, Hiltrud Brauch, Gianluca Severi, Laura Baglietto, Angela Cox, Simon S. Cross, Penelope Miron, Sue M. Gerty, William Tapper, Drakoulis Yannoukakos, George Fountzilas, Peter A. Fasching, Matthias W. Beckmann, Isabel Dos Santos Silva, Julian Peto, Diether Lambrechts, Robert Paridaens, Thomas Rüdiger, Asta Försti, Robert Winqvist, Katri Pylkäs, Robert B. Diasio, Adam M. Lee, Jeanette Eckel-Passow, Celine Vachon, Fiona Blows, Kristy Driver, Alison Dunning, Paul P. D. Pharoah, Kenneth Offit, V. Shane Pankratz, Hakon Hakonarson, Georgia Chenevix-Trench, Douglas F. Easton, Fergus J. Couch

Date Published: 1st Oct 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Alteration of Multiple Leukocyte Gene Expression Networks is Linked with Magnetic Resonance Markers of Prognosis After Acute ST-Elevation Myocardial Infarction.
LIFE Heart

Abstract (Expand)

Prognostic relevant pathways of leukocyte involvement in human myocardial ischemic-reperfusion injury are largely unknown. We enrolled 136 patients with ST-elevation myocardial infarction (STEMI) after … primary angioplasty within 12 h after onset of symptoms. Following reperfusion, whole blood was collected within a median time interval of 20 h (interquartile range: 15-25 h) for genome-wide gene expression analysis. Subsequent CMR scans were performed using a standard protocol to determine infarct size (IS), area at risk (AAR), myocardial salvage index (MSI) and the extent of late microvascular obstruction (lateMO). We found 398 genes associated with lateMO and two genes with IS. Neither AAR, nor MSI showed significant correlations with gene expression. Genes correlating with lateMO were strongly related to several canonical pathways, including positive regulation of T-cell activation (p = 3.44 x 10(-5)), and regulation of inflammatory response (p = 1.86 x 10(-3)). Network analysis of multiple gene expression alterations associated with larger lateMO identified the following functional consequences: facilitated utilisation and decreased concentration of free fatty acid, repressed cell differentiation, enhanced phagocyte movement, increased cell death, vascular disease and compensatory vasculogenesis. In conclusion, the extent of lateMO after acute, reperfused STEMI correlated with altered activation of multiple genes related to fatty acid utilisation, lymphocyte differentiation, phagocyte mobilisation, cell survival, and vascular dysfunction.

Authors: A. Teren, H. Kirsten, F. Beutner, M. Scholz, L. M. Holdt, D. Teupser, M. Gutberlet, J. Thiery, G. Schuler, I. Eitel

Date Published: 3rd Feb 2017

Publication Type: Journal article

Human Diseases: myocardial infarction

Alzheimer's Disease FDG PET Imaging Pattern in an Amyloid-Negative Mild Cognitive Impairment Subject.
LIFE Adult

Abstract (Expand)

The revised NIA-AA diagnostic criteria for Alzheimer's disease (AD) and mild cognitive impairment (MCI) due to AD make use of amyloid pathology and neurodegeneration biomarkers which increase the … diagnostic confidence in the majority of patients. However, in daily praxis, cases with conflicting biomarker constellations occur. A MCI subject underwent neuropsychological testing supplemented by FDG and amyloid PET/MRI as well as CSF sampling. In this subject, the biomarkers of Abeta deposition were negative. [18F]FDG PET, however, showed an AD-typical hypometabolism. Further studies are required to determine frequency and relevance of cases with neurodegeneration-first biomarker constellations to improve our understanding on pathogenesis and diagnosis of AD.

Authors: S. Tiepolt, M. Patt, K. T. Hoffmann, M. L. Schroeter, O. Sabri, H. Barthel

Date Published: 25th Sep 2015

Publication Type: Not specified

Human Diseases: cognitive disorder, Alzheimer's disease

Analysis of asthma patients for cryptococcal seroreactivity in an urban German area.
LIFE Adult

Abstract (Expand)

Cryptococcus neoformans is an opportunistic fungal pathogen that causes lung inflammation and meningoencephalitis in immunocompromised patients but is also able to asymptomatically infect immunocompetent … individuals. C. neoformans is found ubiquitously especially in urban areas where it is spread by pigeons, and fungal exposure may predispose for asthma development already at an early age, as soon as confronted with pigeon droppings. In the study presented here, we investigated the presence of specific immunoglobulin G (IgG) against C. neoformans in sera from patients suffering from asthma in comparison to a healthy control cohort, accrued from the Leipzig Research Centre for Civilization Diseases (LIFE). For serological analysis we developed a flow cytometry (FACS) based assay specific for an acapsular strain of C. neoformans to comprehensively analyze different cryptococcal serotypes. Compared with the non-asthmatic cohort, asthmatics exhibited, as expected, an elevated level of total serum immunoglobulin E (IgE), whereas the IgG seroreactivity against C. neoformans was not significantly different among the two groups (P = .118). Nevertheless, there was a trend toward increased Cryptococcus-specific IgG antibodies in the serum of asthmatics. Additionally, in male asthmatics an increased IgG-mediated seroreactivity compared to female asthmatics was found. This points to a higher prevalence of subclinical C. neoformans infection in male asthmatics and may support the hypothesis of C. neoformans as a risk factor for the development of asthma in urban areas.

Authors: A. Grahnert, U. Muller, H. von Buttlar, R. Treudler, G. Alber

Date Published: 31st May 2015

Publication Type: Not specified

Human Diseases: asthma, allergic hypersensitivity disease

An evaluation of the polymorphisms Ins16bp and Arg72Pro in p53 as breast cancer risk modifiers in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The close functional relationship between p53 and the breast cancer susceptibility genes BRCA1 and BRCA2 has promoted the investigation of various polymorphisms in the p53 gene as possible risk modifiers … in BRCA1/2 mutation carriers. Specifically, two polymorphisms in p53, c.97-147ins16bp and p.Arg72Pro have been analysed as putative breast cancer susceptibility variants, and it has been recently reported that a p53 haplotype combining the absence of the 16-bp insertion and the presence of proline at codon 72 (No Ins-72Pro) was associated with an earlier age at the onset of the first primary tumour in BRCA2 mutation carriers in the Spanish population. In this study, we have evaluated this association in a series of 2932 BRCA1/2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.

Authors: A. Osorio, M. Pollán, G. Pita, R. K. Schmutzler, B. Versmold, C. Engel, A. Meindl, N. Arnold, S. Preisler-Adams, D. Niederacher, W. Hofmann, D. Gadzicki, A. Jakubowska, U. Hamann, J. Lubinski, A. Toloczko-Grabarek, C. Cybulski, T. Debniak, G. Llort, D. Yannoukakos, O. Díez, B. Peissel, P. Peterlongo, P. Radice, T. Heikkinen, H. Nevanlinna, P. L. Mai, J. T. Loud, L. McGuffog, A. C. Antoniou, J. Benitez

Date Published: 1st Sep 2008

Publication Type: Journal article

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

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA …A alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Authors: Sophie Blein, Claire Bardel, Vincent Danjean, Lesley McGuffog, Sue Healey, Daniel Barrowdale, Andrew Lee, Joe Dennis, Karoline B. Kuchenbaecker, Penny Soucy, Mary Beth Terry, Wendy K. Chung, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Susan L. Neuhausen, Yuan Chun Ding, Anne-Marie Gerdes, Bent Ejlertsen, Finn C. Nielsen, Thomas vO Hansen, Ana Osorio, Javier Benitez, Raquel Andrés Conejero, Ena Segota, Jeffrey N. Weitzel, Margo Thelander, Paolo Peterlongo, Paolo Radice, Valeria Pensotti, Riccardo Dolcetti, Bernardo Bonanni, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Siranoush Manoukian, Liliana Varesco, Gabriele L. Capone, Laura Papi, Laura Ottini, Drakoulis Yannoukakos, Irene Konstantopoulou, Judy Garber, Ute Hamann, Alan Donaldson, Angela Brady, Carole Brewer, Claire Foo, D. Gareth Evans, Debra Frost, Diana Eccles, Fiona Douglas, Jackie Cook, Julian Adlard, Julian Barwell, Lisa Walker, Louise Izatt, Lucy E. Side, M. John Kennedy, Marc Tischkowitz, Mark T. Rogers, Mary E. Porteous, Patrick J. Morrison, Radka Platte, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Trevor Cole, Andrew K. Godwin, Claudine Isaacs, Kathleen Claes, Kim de Leeneer, Alfons Meindl, Andrea Gehrig, Barbara Wappenschmidt, Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Hansjoerg Plendl, Karin Kast, Kerstin Rhiem, Nina Ditsch, Norbert Arnold, Raymonda Varon-Mateeva, Rita K. Schmutzler, Sabine Preisler-Adams, Nadja Bogdanova Markov, Shan Wang-Gohrke, Antoine de Pauw, Cédrick Lefol, Christine Lasset, Dominique Leroux, Etienne Rouleau, Francesca Damiola, Hélène Dreyfus, Laure Barjhoux, Lisa Golmard, Nancy Uhrhammer, Valérie Bonadona, Valérie Sornin, Yves-Jean Bignon, Jonathan Carter, Linda van Le, Marion Piedmonte, Paul A. DiSilvestro, Miguel de La Hoya, Trinidad Caldes, Heli Nevanlinna, Kristiina Aittomäki, Agnes Jager, Ans Mw van den Ouweland, Carolien M. Kets, Cora M. Aalfs, Flora E. van Leeuwen, Frans Bl Hogervorst, Hanne Ej Meijers-Heijboer, Jan C. Oosterwijk, Kees Ep van Roozendaal, Matti A. Rookus, Peter Devilee, Rob B. van der Luijt, Edith Olah, Orland Diez, Alex Teulé, Conxi Lazaro, Ignacio Blanco, Jesús Del Valle, Anna Jakubowska, Grzegorz Sukiennicki, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Bjarni A. Agnarsson, Christine Maugard, Alberto Amadori, Marco Montagna, Manuel R. Teixeira, Amanda B. Spurdle, William Foulkes, Curtis Olswold, Noralane M. Lindor, Vernon S. Pankratz, Csilla I. Szabo, Anne Lincoln, Lauren Jacobs, Marina Corines, Mark Robson, Joseph Vijai, Andreas Berger, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Mark H. Greene, Phuong L. Mai, Gad Rennert, Evgeny N. Imyanitov, Anna Marie Mulligan, Gord Glendon, Irene L. Andrulis, Sandrine Tchatchou, Amanda Ewart Toland, Inge Sokilde Pedersen, Mads Thomassen, Torben A. Kruse, Uffe Birk Jensen, Maria A. Caligo, Eitan Friedman, Jamal Zidan, Yael Laitman, Annika Lindblom, Beatrice Melin, Brita Arver, Niklas Loman, Richard Rosenquist, Olufunmilayo I. Olopade, Robert L. Nussbaum, Susan J. Ramus, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Banu K. Arun, Gillian Mitchell, Beth Y. Karlan, Jenny Lester, Sandra Orsulic, Dominique Stoppa-Lyonnet, Gilles Thomas, Jacques Simard, Fergus J. Couch, Kenneth Offit, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Sylvie Mazoyer, Catherine M. Phelan, Olga M. Sinilnikova, David G. Cox

Date Published: 1st Dec 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Assess, compare and enhance the status of Persons with Multiple Sclerosis (MS) in Europe: a European Register for MS.
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

OBJECTIVES: Persons with multiple sclerosis (PwMS) experience health-related quality of life (HRQoL) problems greatly differing across Europe, and the European Union (EU) faces deep inequalities in MS … management from country to country. Through the establishment of a European MS Register (EUReMS), an effective action is proposed to improve the overall knowledge on MS and support effective intervention programmes at EU and national political level. EUReMS aims to achieve consensus on its mission and vision, to define existing data providers, to develop models driving future MS health policies and research, to develop an information technology (IT) infrastructure for a data set, to develop a European shared governance and to secure providers' data provision into EUReMS. MATERIALS AND METHODS: EUReMS is meant to build on a minimum set of core data from existing national and regional population-based MS registries and from PwMS' perspectives. EUReMS' main partner is the European MS Platform (EMSP) acting in collaboration with associated and collaborating European partners. RESULTS: EUReMS was launched in July 2011. A Consensus Statement on purposes, vision, mission and strategies was produced in December 2011, and a comprehensive survey on existing MS data collections in Europe has been performed, and the EUReMS data mask is currently being discussed. CONCLUSIONS: EUReMS will represent a tool to provide up to date, comparable and sustainable MS data through an effective and credible register, which will encourage extensive knowledge building of MS, more equitable policies and higher standards in MS treatment and services.

Authors: M. Pugliatti, D. Eskic, T. Mikolcic, D. Pitschnau-Michel, K. M. Myhr, J. Sastre-Garriga, S. Otero, L. Wieczynska, C. Torje, E. Holloway, O. Rienhoff, T. Friede, K. Buckow, D. Ellenberger, J. Hillert, A. Glaser, P. Flachenecker, J. Fuge, T. Schyns-Liharska, E. Kasilingam, A. Moretti, C. Thalheim

Date Published: 3rd Jan 2013

Publication Type: Not specified

Human Diseases: dementia, Alzheimer's disease

Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer … in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values \textgreater 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients’ survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Authors: Ignacio Blanco, Karoline Kuchenbaecker, Daniel Cuadras, Xianshu Wang, Daniel Barrowdale, Gorka Ruiz de Garibay, Pablo Librado, Alejandro Sánchez-Gracia, Julio Rozas, Núria Bonifaci, Lesley McGuffog, Vernon S. Pankratz, Abul Islam, Francesca Mateo, Antoni Berenguer, Anna Petit, Isabel Català, Joan Brunet, Lidia Feliubadaló, Eva Tornero, Javier Benítez, Ana Osorio, Teresa Ramón y Cajal, Heli Nevanlinna, Kristiina Aittomäki, Banu K. Arun, Amanda E. Toland, Beth Y. Karlan, Christine Walsh, Jenny Lester, Mark H. Greene, Phuong L. Mai, Robert L. Nussbaum, Irene L. Andrulis, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck, Rosa B. Barkardottir, Anna Jakubowska, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Kathleen Claes, Tom van Maerken, Orland Díez, Thomas V. Hansen, Lars Jønson, Anne-Marie Gerdes, Bent Ejlertsen, Miguel de La Hoya, Trinidad Caldés, Alison M. Dunning, Clare Oliver, Elena Fineberg, Margaret Cook, Susan Peock, Emma McCann, Alex Murray, Chris Jacobs, Gabriella Pichert, Fiona Lalloo, Carol Chu, Huw Dorkins, Joan Paterson, Kai-Ren Ong, Manuel R. Teixeira, Frans B. L. Hogervorst, Annemarie H. van der Hout, Caroline Seynaeve, Rob B. van der Luijt, Marjolijn J. L. Ligtenberg, Peter Devilee, Juul T. Wijnen, Matti A. Rookus, Hanne E. J. Meijers-Heijboer, Marinus J. Blok, Ans M. W. van den Ouweland, Cora M. Aalfs, Gustavo C. Rodriguez, Kelly-Anne A. Phillips, Marion Piedmonte, Stacy R. Nerenstone, Victoria L. Bae-Jump, David M. O’Malley, Elena S. Ratner, Rita K. Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg J. Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Uffe Birk Jensen, Mads Thomassen, Torben A. Kruse, Lenka Foretova, Paolo Peterlongo, Loris Bernard, Bernard Peissel, Giulietta Scuvera, Siranoush Manoukian, Paolo Radice, Laura Ottini, Marco Montagna, Simona Agata, Christine Maugard, Jacques Simard, Penny Soucy, Andreas Berger, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Geschwantler-Kaulich, Muy-Kheng Tea, Georg Pfeiler, Esther M. John, Alex Miron, Susan L. Neuhausen, Mary Beth Terry, Wendy K. Chung, Mary B. Daly, David E. Goldgar, Ramunas Janavicius, Cecilia M. Dorfling, Elisabeth J. van Rensburg, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Andrew K. Godwin, Edith Olah, Steven A. Narod, Gad Rennert, Shani Shimon Paluch, Yael Laitman, Eitan Friedman, Annelie Liljegren, Johanna Rantala, Marie Stenmark-Askmalm, Niklas Loman, Evgeny N. Imyanitov, Ute Hamann, Amanda B. Spurdle, Sue Healey, Jeffrey N. Weitzel, Josef Herzog, David Margileth, Chiara Gorrini, Manel Esteller, Antonio Gómez, Sergi Sayols, Enrique Vidal, Holger Heyn, Dominique Stoppa-Lyonnet, Melanie Léoné, Laure Barjhoux, Marion Fassy-Colcombet, Antoine de Pauw, Christine Lasset, Sandra Fert Ferrer, Laurent Castera, Pascaline Berthet, François Cornelis, Yves-Jean Bignon, Francesca Damiola, Sylvie Mazoyer, Olga M. Sinilnikova, Christopher A. Maxwell, Joseph Vijai, Mark Robson, Noah Kauff, Marina J. Corines, Danylko Villano, Julie Cunningham, Adam Lee, Noralane Lindor, Conxi Lázaro, Douglas F. Easton, Kenneth Offit, Georgia Chenevix-Trench, Fergus J. Couch, Antonis C. Antoniou, Miguel Angel Pujana

Date Published: 1st Apr 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association analysis identifies 65 new breast cancer risk loci
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer … risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P \textless 5 \times 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Authors: Kyriaki Michailidou, Sara Lindström, Joe Dennis, Jonathan Beesley, Shirley Hui, Siddhartha Kar, Audrey Lemaçon, Penny Soucy, Dylan Glubb, Asha Rostamianfar, Manjeet K. Bolla, Qin Wang, Jonathan Tyrer, Ed Dicks, Andrew Lee, Zhaoming Wang, Jamie Allen, Renske Keeman, Ursula Eilber, Juliet D. French, Xiao Qing Chen, Laura Fachal, Karen McCue, Amy E. McCart Reed, Maya Ghoussaini, Jason S. Carroll, Xia Jiang, Hilary Finucane, Marcia Adams, Muriel A. Adank, Habibul Ahsan, Kristiina Aittomäki, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Banu Arun, Paul L. Auer, François Bacot, Myrto Barrdahl, Caroline Baynes, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Judith S. Brand, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Louise Brinton, Per Broberg, Ian W. Brock, Annegien Broeks, Angela Brooks-Wilson, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Katja Butterbach, Qiuyin Cai, Hui Cai, Trinidad Caldés, Federico Canzian, Angel Carracedo, Brian D. Carter, Jose E. Castelao, Tsun L. Chan, Ting-Yuan David Cheng, Kee Seng Chia, Ji-Yeob Choi, Hans Christiansen, Christine L. Clarke, Margriet Collée, Don M. Conroy, Emilie Cordina-Duverger, Sten Cornelissen, David G. 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, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Mingajeva Elvira, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Valerie Gaborieau, Marike Gabrielson, Manuela Gago-Dominguez, Yu-Tang Gao, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Nathalie Hamel, Susan Hankinson, Patricia Harrington, Steven N. Hart, Jaana M. Hartikainen, Mikael Hartman, Alexander Hein, Jane Heyworth, Belynda Hicks, Peter Hillemanns, Dona N. Ho, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Ming-Feng Hou, Chia-Ni Hsiung, Guanmengqian Huang, Keith Humphreys, Junko Ishiguro, Hidemi Ito, Motoki Iwasaki, Hiroji Iwata, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Kristine Jones, Michael Jones, Arja Jukkola-Vuorinen, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Daehee Kang, Yoshio Kasuga, Michael J. Kerin, Sofia Khan, Elza Khusnutdinova, Johanna I. Kiiski, Sung-Won Kim, Julia A. Knight, Veli-Matti Kosma, Vessela N. Kristensen, Ute Krüger, Ava Kwong, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Min Hyuk Lee, Jong Won Lee, Chuen Neng Lee, Flavio Lejbkowicz, Jingmei Li, Jenna Lilyquist, Annika Lindblom, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Artitaya Lophatananon, Jan Lubinski, Craig Luccarini, Michael P. Lux, Edmond S. K. Ma, Robert J. MacInnis, Tom Maishman, Enes Makalic, Kathleen E. Malone, Ivana Maleva Kostovska, Arto Mannermaa, Siranoush Manoukian, JoAnn E. Manson, Sara Margolin, Shivaani Mariapun, Maria Elena Martinez, Keitaro Matsuo, Dimitrios Mavroudis, James McKay, Catriona McLean, Hanne Meijers-Heijboer, Alfons Meindl, Primitiva Menéndez, Usha Menon, Jeffery Meyer, Hui Miao, Nicola Miller, Nur Aishah Mohd Taib, Kenneth Muir, Anna Marie Mulligan, Claire Mulot, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Sune F. Nielsen, Dong-Young Noh, Børge G. Nordestgaard, Aaron Norman, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Curtis Olswold, Nick Orr, V. Shane Pankratz, Sue K. Park, Tjoung-Won Park-Simon, Rachel Lloyd, Jose I. A. Perez, Paolo Peterlongo, Julian Peto, Kelly-Anne Phillips, Mila Pinchev, Dijana Plaseska-Karanfilska, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Elizabeth Pugh, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Gadi Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Jane Romm, Kathryn J. Ruddy, Thomas Rüdiger, Anja Rudolph, Matthias Ruebner, Emiel J. T. Rutgers, Emmanouil Saloustros, Dale P. Sandler, Suleeporn Sangrajrang, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Peter Schürmann, Rodney J. Scott, Christopher Scott, Sheila Seal, Caroline Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Grace Sheng, Mark E. Sherman, Martha J. Shrubsole, Xiao-Ou Shu, Ann Smeets, Christof Sohn, Melissa C. Southey, John J. Spinelli, Christa Stegmaier, Sarah Stewart-Brown, Jennifer Stone, Daniel O. Stram, Harald Surowy, Anthony Swerdlow, Rulla Tamimi, Jack A. Taylor, Maria Tengström, Soo H. Teo, Mary Beth Terry, Daniel C. Tessier, Somchai Thanasitthichai, Kathrin Thöne, Rob A. E. M. Tollenaar, Ian Tomlinson, Ling Tong, Diana Torres, Thérèse Truong, Chiu-Chen Tseng, Shoichiro Tsugane, Hans-Ulrich Ulmer, Giske Ursin, Michael Untch, Celine Vachon, Christi J. van Asperen, David van den Berg, Ans M. W. van den Ouweland, Lizet van der Kolk, Rob B. van der Luijt, Daniel Vincent, Jason Vollenweider, Quinten Waisfisz, Shan Wang-Gohrke, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter Willett, Robert Winqvist, Alicja Wolk, Anna H. Wu, Lucy Xia, Taiki Yamaji, Xiaohong R. Yang, Cheng Har Yip, Keun-Young Yoo, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Bin Zhu, Argyrios Ziogas, Elad Ziv, Sunil R. Lakhani, Antonis C. Antoniou, Arnaud Droit, Irene L. Andrulis, Christopher I. Amos, Fergus J. Couch, Paul D. P. Pharoah, Jenny Chang-Claude, Per Hall, David J. Hunter, Roger L. Milne, Montserrat García-Closas, Marjanka K. Schmidt, Stephen J. Chanock, Alison M. Dunning, Stacey L. Edwards, Gary D. Bader, Georgia Chenevix-Trench, Jacques Simard, Peter Kraft, Douglas F. Easton

Date Published: 1st Nov 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Importance Germline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2, explain fewer than half of all …l familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C\textgreaterT (p.GIn1701Ter [rs147021911]) and c.5791C\textgreaterT (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM gene in familial index cases and geographically matched controls is pending. Objectives To assess the mutational spectrum within the FANCM gene, and to determine a potential association of LoF germline mutations within the FANCM gene with BC and/or OC risk. Design, Setting, and Participants For the purpose of identification and characterization of novel BC and/or OC predisposition genes, a total of 2047 well-characterized familial BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for LoF mutations within the FANCM gene by next-generation sequencing. All patients previously tested negative for pathogenic BRCA1 and BRCA2 mutations. All data collection occurred between June 1, 2013, and April 30, 2016. Data analysis was performed from May 1, 2016, to July 1, 2016. Main Outcomes and Measures FANCM LoF mutation frequencies in patients with BC and/or OC were compared with the FANCM LoF mutation frequencies in geographically matched controls by univariate logistic regression. Positive associations were stratified by age at onset and cancer family history. Results In this case-control study, 2047 well-characterized familial female BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for truncating FANCM alterations. Heterozygous LoF mutations within the FANCM gene were significantly associated with familial BC risk, with an overall odds ratio (OR) of 2.05 (95% CI, 0.94-4.54; P = .049) and a mutation frequency of 1.03% in index cases. In familial patients whose BC onset was before age 51 years, an elevated OR of 2.44 (95% CI, 1.08-5.59; P = .02) was observed. A more pronounced association was identified for patients with a triple-negative BC tumor phenotype (OR, 3.75; 95% CI, 1.00-12.85; P = .02). No significant association was detected for unselected OC cases (OR, 1.74; 95% CI, 0.57-5.08; P = .27). Conclusions and Relevance Based on the significant associations of heterozygous LoF mutations with early-onset or triple-negative BC, FANCM should be included in diagnostic gene panel testing for individual risk assessment. Larger studies are required to determine age-dependent disease risks for BC and to assess a potential role of FANCM mutations in OC pathogenesis.

Authors: Guido Neidhardt, Jan Hauke, Juliane Ramser, Eva Groß, Andrea Gehrig, Clemens R. Müller, Anne-Karin Kahlert, Karl Hackmann, Ellen Honisch, Dieter Niederacher, Stefanie Heilmann-Heimbach, André Franke, Wolfgang Lieb, Holger Thiele, Janine Altmüller, Peter Nürnberg, Kristina Klaschik, Corinna Ernst, Nina Ditsch, Frank Jessen, Alfredo Ramirez, Barbara Wappenschmidt, Christoph Engel, Kerstin Rhiem, Alfons Meindl, Rita K. Schmutzler, Eric Hahnen

Date Published: 1st Sep 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association between mental demands at work and cognitive functioning in the general population - results of the health study of the Leipzig research center for civilization diseases (LIFE).
LIFE Adult

Abstract (Expand)

BACKGROUND: The level of mental demands in the workplace is rising. The present study investigated whether and how mental demands at work are associated with cognitive functioning in the general … population. METHODS: The analysis is based on data of the Health Study of the Leipzig Research Centre for Civilization Disease (LIFE). 2,725 participants aged 40-80 years underwent cognitive testing (Trail-Making Test, Verbal Fluency Test) and provided information on their occupational situation. Participants over the age of 65 years additionally completed the Mini-Mental State Examination. Mental demands at work were rated by a standardized classification system (O*NET). The association between mental demands and cognitive functioning was analyzed using Generalized Linear Modeling (GENLIN) adjusted for age, gender, self-regulation, working hour status, education, and health-related factors. RESULTS: Univariate as well as multivariate analyses demonstrated significant and highly consistent effects of higher mental demands on better performance in cognitive testing. The results also indicated that the effects are independent of education and intelligence. Moreover, analyses of retired individuals implied a significant association between high mental demands at work of the job they once held and a better cognitive functioning in old age. CONCLUSIONS: In sum, our findings suggest a significant association between high mental demands at work and better cognitive functioning. In this sense, higher levels of mental demands - as brought about by technological changes in the working environment - may also have beneficial effects for the society as they could increase cognitive capacity levels and might even delay cognitive decline in old age.

Authors: F. S. Then, T. Luck, M. Luppa, K. Arelin, M. L. Schroeter, C. Engel, M. Loffler, J. Thiery, A. Villringer, S. G. Riedel-Heller

Date Published: 11th Jun 2014

Publication Type: Not specified

Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate …e whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. METHODS Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. RESULTS We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 \times 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. CONCLUSION We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.

Authors: Yosr Hamdi, Penny Soucy, Karoline B. Kuchenbaeker, Tomi Pastinen, Arnaud Droit, Audrey Lemaçon, Julian Adlard, Kristiina Aittomäki, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Anita Bane, Laure Barjhoux, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Marinus J. Blok, Kristie Bobolis, Valérie Bonadona, Bernardo Bonanni, Angela R. Bradbury, Carole Brewer, Bruno Buecher, Saundra S. Buys, Maria A. Caligo, Jocelyne Chiquette, Wendy K. Chung, Kathleen B. M. Claes, Mary B. Daly, Francesca Damiola, Rosemarie Davidson, Miguel de La Hoya, Kim de Leeneer, Orland Diez, Yuan Chun Ding, Riccardo Dolcetti, Susan M. Domchek, Cecilia M. Dorfling, Diana Eccles, Ros Eeles, Zakaria Einbeigi, Bent Ejlertsen, Christoph Engel, D. Gareth Evans, Lidia Feliubadalo, Lenka Foretova, Florentia Fostira, William D. Foulkes, George Fountzilas, Eitan Friedman, Debra Frost, Pamela Ganschow, Patricia A. Ganz, Judy Garber, Simon A. Gayther, Anne-Marie Gerdes, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Mark H. Greene, Jacek Gronwald, Eric Hahnen, Ute Hamann, Thomas v. O. Hansen, Steven Hart, John L. Hays, Frans B. L. Hogervorst, Peter J. Hulick, Evgeny N. Imyanitov, Claudine Isaacs, Louise Izatt, Anna Jakubowska, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Esther M. John, Vijai Joseph, Walter Just, Katarzyna Kaczmarek, Beth Y. Karlan, Carolien M. Kets, Judy Kirk, Mieke Kriege, Yael Laitman, Maïté Laurent, Conxi Lazaro, Goska Leslie, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Niklas Loman, Jennifer T. Loud, Siranoush Manoukian, Milena Mariani, Sylvie Mazoyer, Lesley McGuffog, Hanne E. J. Meijers-Heijboer, Alfons Meindl, Austin Miller, Marco Montagna, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Robert L. Nussbaum, Edith Olah, Olufunmilayo I. Olopade, Kai-Ren Ong, Jan C. Oosterwijk, Ana Osorio, Laura Papi, Sue Kyung Park, Inge Sokilde Pedersen, Bernard Peissel, Pedro Perez Segura, Paolo Peterlongo, Catherine M. Phelan, Paolo Radice, Johanna Rantala, Christine Rappaport-Fuerhauser, Gad Rennert, Andrea Richardson, Mark Robson, Gustavo C. Rodriguez, Matti A. Rookus, Rita Katharina Schmutzler, Nicolas Sevenet, Payal D. Shah, Christian F. Singer, Thomas P. Slavin, Katie Snape, Johanna Sokolowska, Ida Marie Heeholm Sønderstrup, Melissa Southey, Amanda B. Spurdle, Zsofia Stadler, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Christian Sutter, Yen Tan, Muy-Kheng Tea, Manuel R. Teixeira, Alex Teulé, Soo-Hwang Teo, Mary Beth Terry, Mads Thomassen, Laima Tihomirova, Marc Tischkowitz, Silvia Tognazzo, Amanda Ewart Toland, Nadine Tung, Ans M. W. van den Ouweland, Rob B. van der Luijt, Klaartje van Engelen, Elizabeth J. van Rensburg, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Juul T. Wijnen, Timothy Rebbeck, Georgia Chenevix-Trench, Kenneth Offit, Fergus J. Couch, Silje Nord, Douglas F. Easton, Antonis C. Antoniou, Jacques Simard

Date Published: 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association of death receptor 4 variant (683A C) with ovarian cancer risk in BRCA1 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Dysregulation of apoptosis plays an important role in carcinogenesis. Therefore, apoptosis-associated genes like the death receptor 4 (DR4, TRAIL-R1) are interesting candidates for modifying the … penetrance of breast and ovarian cancer in carriers of BRCA1 and BRCA2 mutations. The DR-4 haplotype 626C-683C [626C \textgreater G, Thr209Arg (rs4871857) and 683A \textgreater C, Glu228Ala (rs17088993)] has recently been linked to an increased risk of breast cancer. To evaluate whether DR4 626C \textgreater G or DR4 683A \textgreater C modifies the risk of breast or ovarian cancer in carriers of BRCA1 and BRCA2 mutations, we undertook a national multicenter study including data of 840 carriers of breast cancer gene (BRCA) mutations. DNA samples were collected from 12 German research centers between 1996 and 2005 and were genotyped by the Taqman allelic discrimination assay. The association between genotypes and incidence of breast or ovarian cancer data was evaluated using a Cox proportional hazards regression model. We found evidence for a significant association of DR4 683A \textgreater C with a higher risk for ovarian cancer in carriers of BRCA1 mutations [n = 557, hazard ratio 1.78 (1.24-2.55), p = 0.009]. Our results thus indicate that the DR4 683A \textgreater C variant modifies the risk of ovarian cancer in carriers of BRCA1 mutations.

Authors: Michelle G. Dick, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Raymonda Varon-Mateeva, Christian Sutter, Dieter Niederacher, Helmut Deissler, Sabine Preisler-Adams, Karin Kast, Dieter Schäfer, Dorothea Gadzicki, Wolfram Heinritz, Barbara Wappenschmidt, Rita K. Schmutzler

Date Published: 15th Mar 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer (PCa). We evaluated whether PSVs in BRCA1/2 were associated with risk … of overall PCa or high grade (Gleason 8+) PCa using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with PCa, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without PCa. PSVs in the 3’ region of BRCA2 (c.7914+) were significantly associated with elevated risk of PCa compared with reference bin c.1001-c.7913 (HR=1.78, 95%CI: 1.25-2.52, p=0.001), as well as elevated risk of Gleason 8+ PCa (HR=3.11, 95%CI: 1.63-5.95, p=0.001). c.756-c.1000 was also associated with elevated PCa risk (HR=2.83, 95%CI: 1.71-4.68, p=0.00004) and elevated risk of Gleason 8+ PCa (HR=4.95, 95%CI: 2.12-11.54, p=0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive PCa.

Authors: Vivek L. Patel, Evan L. Busch, Tara M. Friebel, Angel Cronin, Goska Leslie, Lesley McGuffog, Julian Adlard, Simona Agata, Bjarni A. Agnarsson, Munaza Ahmed, Kristiina Aittomäki, Elisa Alducci, Irene L. Andrulis, Adalgeir Arason, Norbert Arnold, Grazia Artioli, Brita Arver, Bernd Auber, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel R. Barnes, Alicia Barroso, Daniel Barrowdale, Muriel Belotti, Javier Benitez, Brigitte Bertelsen, Marinus J. Blok, Istvan Bodrogi, Valérie Bonadona, Bernardo Bonanni, Davide Bondavalli, Susanne E. Boonen, Julika Borde, Ake Borg, Angela R. Bradbury, Angela Brady, Carole Brewer, Joan Brunet, Bruno Buecher, Saundra S. Buys, Santiago Cabezas-Camarero, Trinidad Caldés, Almuth Caliebe, Maria A. Caligo, Mariarosaria Calvello, Ian G. Campbell, Ileana Carnevali, Estela Carrasco, Tsun L. Chan, Annie T. W. Chu, Wendy K. Chung, Kathleen B. M. Claes, Gemo Study Collaborators, Embrace Collaborators, Jackie Cook, Laura Cortesi, Fergus J. Couch, Mary B. Daly, Giuseppe Damante, Esther Darder, Rosemarie Davidson, Miguel de La Hoya, Lara Della Puppa, Joe Dennis, Orland Díez, Yuan Chun Ding, Nina Ditsch, Susan M. Domchek, Alan Donaldson, Bernd Dworniczak, Douglas F. Easton, Diana M. Eccles, Rosalind A. Eeles, Hans Ehrencrona, Bent Ejlertsen, Christoph Engel, D. Gareth Evans, Laurence Faivre, Ulrike Faust, Lídia Feliubadaló, Lenka Foretova, Florentia Fostira, George Fountzilas, Debra Frost, Vanesa García-Barberán, Pilar Garre, Marion Gauthier-Villars, Lajos Géczi, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Giuseppe Giannini, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Mark H. Greene, Angelica M. Gutierrez-Barrera, Eric Hahnen, Ute Hamann, Jan Hauke, Natalie Herold, Frans B. L. Hogervorst, Ellen Honisch, John L. Hopper, Peter J. Hulick, Kconfab Investigators, Hebon Investigators, Louise Izatt, Agnes Jager, Paul James, Ramunas Janavicius, Uffe Birk Jensen, Thomas Dyrso Jensen, Oskar Th Johannsson, Esther M. John, Vijai Joseph, Eunyoung Kang, Karin Kast, Johanna I. Kiiski, Sung-Won Kim, Zisun Kim, Kwang-Pil Ko, Irene Konstantopoulou, Gero Kramer, Lotte Krogh, Torben A. Kruse, Ava Kwong, Mirjam Larsen, Christine Lasset, Charlotte Lautrup, Conxi Lázaro, Jihyoun Lee, Jong Won Lee, Min Hyuk Lee, Johannes Lemke, Fabienne Lesueur, Annelie Liljegren, Annika Lindblom, Patricia Llovet, Adria Lopez-Fernández, Irene Lopez-Perolio, Victor Lorca, Jennifer T. Loud, Edmond S. K. Ma, Phuong L. Mai, Siranoush Manoukian, Veronique Mari, Lynn Martin, Laura Matricardi, Noura Mebirouk, Veronica Medici, Hanne E. J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Clare Miller, Denise Molina Gomes, Marco Montagna, Thea M. Mooij, Lidia Moserle, Emmanuelle Mouret-Fourme, Anna Marie Mulligan, Katherine L. Nathanson, Marie Navratilova, Heli Nevanlinna, Dieter Niederacher, Finn C. Cilius Nielsen, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Kai-Ren Ong, Ana Osorio, Claus-Eric Ott, Domenico Palli, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Pedro Pérez-Segura, Paolo Peterlongo, Annabeth Høgh Petersen, Mary E. Porteous, Miguel Angel Pujana, Paolo Radice, Juliane Ramser, Johanna Rantala, Muhammad U. Rashid, Kerstin Rhiem, Piera Rizzolo, Mark E. Robson, Matti A. Rookus, Caroline Maria Rossing, Kathryn J. Ruddy, Catarina Santos, Claire Saule, Rosa Scarpitta, Rita K. Schmutzler, Hélène Schuster, Leigha Senter, Caroline M. Seynaeve, Payal D. Shah, Priyanka Sharma, Vivian Y. Shin, Valentina Silvestri, Jacques Simard, Christian F. Singer, Anne-Bine Skytte, Katie Snape, Angela R. Solano, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Linda Steele, Doris Steinemann, Dominique Stoppa-Lyonnet, Agostina Stradella, Lone Sunde, Christian Sutter, Yen Y. Tan, Manuel R. Teixeira, Soo Hwang Teo, Mads Thomassen, Maria Grazia Tibiletti, Marc Tischkowitz, Silvia Tognazzo, Amanda E. Toland, Stefania Tommasi, Diana Torres, Angela Toss, Alison H. Trainer, Nadine Tung, Christi J. van Asperen, Frederieke H. van der Baan, Lizet E. van der Kolk, Rob B. van der Luijt, Liselotte P. van Hest, Liliana Varesco, Raymonda Varon-Mateeva, Alessandra Viel, Jeroen Vierstraete, Roberta Villa, Anna von Wachenfeldt, Philipp Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Greet Wieme, Siddhartha Yadav, Drakoulis Yannoukakos, Sook-Yee Yoon, Cristina Zanzottera, Kristin K. Zorn, Anthony V. D’Amico, Matthew L. Freedman, Mark M. Pomerantz, Georgia Chenevix-Trench, Antonis C. Antoniou, Susan L. Neuhausen, Laura Ottini, Henriette Roed Nielsen, Timothy R. Rebbeck

Date Published: 13th Nov 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

ASSOCIATION OF HIPPOCAMPAL VOLUMES WITH COGNITIVE TASKS IN A LARGE POPULATION-BASED COHORT
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Background: Hippocampal volume, assessed via high-resolution MRI, is associated with memory and visuospatial performance in humans (Squire, 2004) and specifically prone to develop atrophy with age … (Apostolova,2015). This process has been linked to neurodegenerative diseases, such as Alzheimer’s disease (Apostolova,2015) and a decline of cognitive functions (Bruno,2016). However, due to differences in study-design and characteristics certain heterogeneity in results remains, in particular considering subfieldspecific effects (deFlores,2015). Therefore, we aim to determine the association of volumes of the whole hippocampus and its subfields on cognition in a large population-based cohort. Methods: Subjects: 1956 healthy participants from the Leipzig Research-Center-for-Civilization-Disease, aged 19-82years with MRI and neuropsychological tests (mean-age=57.61,±15.08SD). Exclusion: stroke, major-brain-pathologies, central-nervous-medication. Independent Variables: Volume of hippocampus and its subfields (CornuAmmonis1, 2-3, 4-DentateGyrus,(Pre-)subiculum). Dependent Variables: Verbal word-list learning, verbal-fluency, TrailMakingTask-(TMT)-A&B. Covariates: sex, age, years-of-education, total grey-mattervolume Image Analysis on high-resolution T1-images assessed at 3T. Hippocampal volumes were estimated using automatic segmentation analysis implemented in FreeSurfer (www.freesurfer.net). Statistical Analysis: Independent and dependent variables were first entered into Pearson Correlations. Variables with a correlation coefficient of r>0.1 were entered into multiple linear-regressions and adjusted for potential confounding(forward inclusion-model). Results: According to bivariate correlations, better performance in verbal-learning, verbal-fluency and TMT-A&B correlated moderately with larger whole-hippocampal volume and the volumes of all subfields(all |r|>0.102, all p0.046, all p0.5). Conclusions: Using a large cross-sectional cohort of healthy adults we found that volumes of the whole-hippocampus and subfields covering the CA4/dentate-gyrus region were weakly, yet specifically associated with verbal-learning and spatial processing-speed. Our preliminary results are in line with previous studies presuming a differential involvement of the hippocampus in tasks of verbal-learning and spatial processing (Oosterman,2010). Upcoming analyses implementing parcellation along the anteriorposterior- axis and random-effect-models might help to further disentangle these effects.

Authors: S. Huhn, R. Zhang, Frauke Beyer, L. Lampe, T. Luck, S. G. Riedel-Heller, M. L. Schroeter, Markus Löffler, M. Stumvoll, A. Villringer, A. V. Witte

Date Published: 1st Jul 2017

Publication Type: Not specified

Human Diseases: cognitive disorder, dementia

Association of hormone receptor status with grading, age of onset, and tumor size in BRCA1-associated breast cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BRCA1-associated breast cancer frequently presents with estrogen-receptor (ERalpha) and progesterone-receptor (PR) negativity, grade 3, and early onset. In contrast, in BRCA1-deficient mice, ERalpha … is highly expressed in early tumorigenesis. In a retrospective cohort study on 587 breast cancer patients with deleterious BRCA1 mutations, the correlation of ER, PR status, grading, age of onset, and tumor size was investigated. ERalpha and PR expression decreased from 62% in ductal carcinoma in situ (DCIS) to 20% and 16% in pT3, respectively (p value for ER 0.025 and PR 0.035, Fisher’s exact test). The percentage of grade 1/2 tumors decreased from 44% in DCIS to 17% in pT3 (p value 0.074). Moreover, ER/PR positivity increased with increasing age. Our data suggest that early stage BRCA1-associated breast cancers are more frequently ERalpha and PR positive and low grade than advanced stages.

Authors: M. Graeser, K. Bosse, M. Brosig, C. Engel, R. K. Schmutzler

Date Published: 1st May 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association of the apolipoprotein E genotype with memory performance and executive functioning in cognitively intact elderly.
LIFE Adult

Abstract (Expand)

OBJECTIVE: To test for a possible effect of the apolipoprotein E epsilon 4 (APOE epsilon4) allele on memory performance and executive functioning (EF) in cognitively intact elderly. METHOD: The authors … studied 202 randomly selected and cognitively intact older adults (65+ years) of the Leipzig Research Center for Civilization Diseases Health Care Study. Intact global cognitive functioning was defined using a Mini-Mental Status Examination (MMSE) score >/= 28. Performance in memory was assessed with the CERAD Word List and Constructional Praxis Recall, performance in EF with the Trail Making Test Part B (TMT-B). Multivariable linear regressions were used to evaluate the association between cognitive performance and APOE status, controlled for covariates. RESULTS: Among the cognitively intact older adults, 21.3% (n = 43) were carriers of the APOE epsilon4 allele. Carriers did not differ significantly from noncarriers in terms of age, gender, intelligence level, or performance in memory but showed a significantly lower TMT-B performance as a measure of EF (TMT-B M time/SD = 105.6/36.2 vs. 91.9/32.7 s; Mann-Whitney U = 4,313.000; p = .009). The association between lower TMT-B performance and APOE epsilon4 genotype remained significant in multivariable linear regression analysis. Similar findings were found for the subsample of those 78 elderly, who reached a perfect MMSE-score of 30. CONCLUSIONS: A lower EF performance in cognitively intact older APOE epsilon4 allele carriers might be related to an early Alzheimer's dementia (AD) prodrome. In this case, a stronger focus on first subtle changes in EF may help to improve early AD detection in those being at genetic risk.

Authors: T. Luck, F. S. Then, M. Luppa, M. L. Schroeter, K. Arelin, R. Burkhardt, J. Thiery, M. Loffler, A. Villringer, S. G. Riedel-Heller

Date Published: 4th Nov 2014

Publication Type: Not specified

Association of the BRCA1 missense variant R1699W with a malignant phyllodes tumor of the breast
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Familial breast carcinomas that are attributable to BRCA1 or BRCA2 mutations have characteristic morphologic and immunhistochemical features. BRCA1-associated carcinomas are poorly differentiated … infiltrating ductal carcinomas frequently exhibiting morphologic features of typical or atypical medullary carcinomas such as prominent lymphocytic infiltrate and pushing margins. We report on a patient carrying the deleterious BRCA1 germline mutation R1699W, who presented with a malignant phyllodes tumor of the breast. The re-investigation of archival material by a reference pathologist of the German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC) revealed BRCA-associated pronounced pushing margins. In a total of 618 unrelated index patients who are registered in the GCHBOC database, no other phyllodes tumor has been described, while 10 carriers of the R1699W mutant have been identified. We conclude that the histopathologic appearance of the phyllodes tumor indicates an association with the BRCA1 mutation R1699W although it is a rare event in BRCA-positive families.

Authors: Kerstin Rhiem, Uta Flucke, Christoph Engel, Barbara Wappenschmidt, Axel Reinecke-Lüthge, Reinhard Büttner, Rita Katharina Schmutzler

Date Published: 1st Jul 2007

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association of the variants CASP8 D302H and CASP10 V410I with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying …g the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. METHODS To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). RESULTS The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85; 95% CI, 0.76-0.97; P(trend) = 0.011) and ovarian cancer (per-allele HR, 0.69; 95% CI, 0.53-0.89; P(trend) = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. CONCLUSIONS CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. IMPACT The combined application of these and other recently identified genetic risk modifiers could in the future allow better individual risk calculation and could aid in the individualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers.

Authors: Christoph Engel, Beatrix Versmold, Barbara Wappenschmidt, Jacques Simard, Douglas F. Easton, Susan Peock, Margaret Cook, Clare Oliver, Debra Frost, Rebecca Mayes, D. Gareth Evans, Rosalind Eeles, Joan Paterson, Carole Brewer, Lesley McGuffog, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Olga M. Sinilnikova, Laure Barjhoux, Marc Frenay, Cécile Michel, Dominique Leroux, Helene Dreyfus, Christine Toulas, Laurence Gladieff, Nancy Uhrhammer, Yves-Jean Bignon, Alfons Meindl, Norbert Arnold, Raymonda Varon-Mateeva, Dieter Niederacher, Sabine Preisler-Adams, Karin Kast, Helmut Deissler, Christian Sutter, Dorothea Gadzicki, Georgia Chenevix-Trench, Amanda B. Spurdle, Xiaoqing Chen, Jonathan Beesley, Håkan Olsson, Ulf Kristoffersson, Hans Ehrencrona, Annelie Liljegren, Rob B. van der Luijt, Theo A. van Os, Flora E. van Leeuwen, Susan M. Domchek, Timothy R. Rebbeck, Katherine L. Nathanson, Ana Osorio, Teresa Ramón y Cajal, Irene Konstantopoulou, Javier Benítez, Eitan Friedman, Bella Kaufman, Yael Laitman, Phuong L. Mai, Mark H. Greene, Heli Nevanlinna, Kristiina Aittomäki, Csilla I. Szabo, Trinidad Caldes, Fergus J. Couch, Irene L. Andrulis, Andrew K. Godwin, Ute Hamann, Rita K. Schmutzler

Date Published: 8th Nov 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

IMPORTANCE Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE To identify mutation-specific cancer risks for carriers …ers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES Breast and ovarian cancer risks. RESULTS Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 \times 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2’, RHR = 1.38; 95% CI, 1.22-1.55; P = 6 \times 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 \times 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1’; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 \times 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Authors: Timothy R. Rebbeck, Nandita Mitra, Fei Wan, Olga M. Sinilnikova, Sue Healey, Lesley McGuffog, Sylvie Mazoyer, Georgia Chenevix-Trench, Douglas F. Easton, Antonis C. Antoniou, Katherine L. Nathanson, Yael Laitman, Anya Kushnir, Shani Paluch-Shimon, Raanan Berger, Jamal Zidan, Eitan Friedman, Hans Ehrencrona, Marie Stenmark-Askmalm, Zakaria Einbeigi, Niklas Loman, Katja Harbst, Johanna Rantala, Beatrice Melin, Dezheng Huo, Olufunmilayo I. Olopade, Joyce Seldon, Patricia A. Ganz, Robert L. Nussbaum, Salina B. Chan, Kunle Odunsi, Simon A. Gayther, Susan M. Domchek, Banu K. Arun, Karen H. Lu, Gillian Mitchell, Beth Y. Karlan, Christine Walsh, Jenny Lester, Andrew K. Godwin, Harsh Pathak, Eric Ross, Mary B. Daly, Alice S. Whittemore, Esther M. John, Alexander Miron, Mary Beth Terry, Wendy K. Chung, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Linda Steele, Susan L. Neuhausen, Yuan Chun Ding, Bent Ejlertsen, Anne-Marie Gerdes, Thomas v. O. Hansen, Teresa Ramón y Cajal, Ana Osorio, Javier Benitez, Javier Godino, Maria-Isabel Tejada, Mercedes Duran, Jeffrey N. Weitzel, Kristie A. Bobolis, Sharon R. Sand, Annette Fontaine, Antonella Savarese, Barbara Pasini, Bernard Peissel, Bernardo Bonanni, Daniela Zaffaroni, Francesca Vignolo-Lutati, Giulietta Scuvera, Giuseppe Giannini, Loris Bernard, Maurizio Genuardi, Paolo Radice, Riccardo Dolcetti, Siranoush Manoukian, Valeria Pensotti, Viviana Gismondi, Drakoulis Yannoukakos, Florentia Fostira, Judy Garber, Diana Torres, Muhammad Usman Rashid, Ute Hamann, Susan Peock, Debra Frost, Radka Platte, D. Gareth Evans, Rosalind Eeles, Rosemarie Davidson, Diana Eccles, Trevor Cole, Jackie Cook, Carole Brewer, Shirley Hodgson, Patrick J. Morrison, Lisa Walker, Mary E. Porteous, M. John Kennedy, Louise Izatt, Julian Adlard, Alan Donaldson, Steve Ellis, Priyanka Sharma, Rita Katharina Schmutzler, Barbara Wappenschmidt, Alexandra Becker, Kerstin Rhiem, Eric Hahnen, Christoph Engel, Alfons Meindl, Stefanie Engert, Nina Ditsch, Norbert Arnold, Hans Jörg Plendl, Christoph Mundhenke, Dieter Niederacher, Markus Fleisch, Christian Sutter, C. R. Bartram, Nicola Dikow, Shan Wang-Gohrke, Dorothea Gadzicki, Doris Steinemann, Karin Kast, Marit Beer, Raymonda Varon-Mateeva, Andrea Gehrig, Bernhard H. Weber, Dominique Stoppa-Lyonnet, Claude Houdayer, Muriel Belotti, Marion Gauthier-Villars, Francesca Damiola, Nadia Boutry-Kryza, Christine Lasset, Hagay Sobol, Jean-Philippe Peyrat, Danièle Muller, Jean-Pierre Fricker, Marie-Agnès Collonge-Rame, Isabelle Mortemousque, Catherine Nogues, Etienne Rouleau, Claudine Isaacs, Anne de Paepe, Bruce Poppe, Kathleen Claes, Kim de Leeneer, Marion Piedmonte, Gustavo Rodriguez, Katie Wakely, John Boggess, Stephanie V. Blank, Jack Basil, Masoud Azodi, Kelly-Anne Phillips, Trinidad Caldes, Miguel de La Hoya, Atocha Romero, Heli Nevanlinna, Kristiina Aittomäki, Annemarie H. van der Hout, Frans B. L. Hogervorst, Senno Verhoef, J. Margriet Collée, Caroline Seynaeve, Jan C. Oosterwijk, Johannes J. P. Gille, Juul T. Wijnen, Encarna B. Gómez Garcia, Carolien M. Kets, Margreet G. E. M. Ausems, Cora M. Aalfs, Peter Devilee, Arjen R. Mensenkamp, Ava Kwong, Edith Olah, Janos Papp, Orland Diez, Conxi Lazaro, Esther Darder, Ignacio Blanco, Mónica Salinas, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Grzegorz Sukiennicki, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Aleksandra Toloczko-Grabarek, Elżbieta Złowocka-Perłowska, Janusz Menkiszak, Adalgeir Arason, Rosa B. Barkardottir, Jacques Simard, Rachel Laframboise, Marco Montagna, Simona Agata, Elisa Alducci, Ana Peixoto, Manuel R. Teixeira, Amanda B. Spurdle, Min Hyuk Lee, Sue K. Park, Sung-Won Kim, Tara M. Friebel, Fergus J. Couch, Noralane M. Lindor, Vernon S. Pankratz, Lucia Guidugli, Xianshu Wang, Marc Tischkowitz, Lenka Foretova, Joseph Vijai, Kenneth Offit, Mark Robson, Rohini Rau-Murthy, Noah Kauff, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Gschwantler-Kaulich, Georg Pfeiler, Muy-Kheng Tea, Andreas Berger, Mark H. Greene, Phuong L. Mai, Evgeny N. Imyanitov, Amanda Ewart Toland, Leigha Senter, Anders Bojesen, Inge Sokilde Pedersen, Anne-Bine Skytte, Lone Sunde, Mads Thomassen, Sanne Traasdahl Moeller, Torben A. Kruse, Uffe Birk Jensen, Maria Adelaide Caligo, Paolo Aretini, Soo-Hwang Teo, Christina G. Selkirk, Peter J. Hulick, Irene Andrulis

Date Published: 7th Apr 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. …. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. METHODS We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. RESULTS The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P \textless10(-6) in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. CONCLUSIONS Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.

Authors: Karoline B. Kuchenbaecker, Susan L. Neuhausen, Mark Robson, Daniel Barrowdale, Lesley McGuffog, Anna Marie Mulligan, Irene L. Andrulis, Amanda B. Spurdle, Marjanka K. Schmidt, Rita K. Schmutzler, Christoph Engel, Barbara Wappenschmidt, Heli Nevanlinna, Mads Thomassen, Melissa Southey, Paolo Radice, Susan J. Ramus, Susan M. Domchek, Katherine L. Nathanson, Andrew Lee, Sue Healey, Robert L. Nussbaum, Timothy R. Rebbeck, Banu K. Arun, Paul James, Beth Y. Karlan, Jenny Lester, Ilana Cass, Mary Beth Terry, Mary B. Daly, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Linda Steele, Thomas v O Hansen, Bent Ejlertsen, Anne-Marie Gerdes, Finn C. Nielsen, Joe Dennis, Julie Cunningham, Steven Hart, Susan Slager, Ana Osorio, Javier Benitez, Mercedes Duran, Jeffrey N. Weitzel, Isaac Tafur, Mary Hander, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Gaia Roversi, Giulietta Scuvera, Bernardo Bonanni, Paolo Mariani, Sara Volorio, Riccardo Dolcetti, Liliana Varesco, Laura Papi, Maria Grazia Tibiletti, Giuseppe Giannini, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Ute Hamann, Alan Donaldson, Carole Brewer, Claire Foo, D. Gareth Evans, Debra Frost, Diana Eccles, Fiona Douglas, Angela Brady, Jackie Cook, Marc Tischkowitz, Julian Adlard, Julian Barwell, Kai-Ren Ong, Lisa Walker, Louise Izatt, Lucy E. Side, M. John Kennedy, Mark T. Rogers, Mary E. Porteous, Patrick J. Morrison, Radka Platte, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Steve Ellis, Andrew K. Godwin, Kerstin Rhiem, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg Plendl, Dieter Niederacher, Christian Sutter, Doris Steinemann, Nadja Bogdanova-Markov, Karin Kast, Raymonda Varon-Mateeva, Shan Wang-Gohrke, Andrea Gehrig, Birgid Markiefka, Bruno Buecher, Cédrick Lefol, Dominique Stoppa-Lyonnet, Etienne Rouleau, Fabienne Prieur, Francesca Damiola, Laure Barjhoux, Laurence Faivre, Michel Longy, Nicolas Sevenet, Olga M. Sinilnikova, Sylvie Mazoyer, Valérie Bonadona, Virginie Caux-Moncoutier, Claudine Isaacs, Tom van Maerken, Kathleen Claes, Marion Piedmonte, Lesley Andrews, John Hays, Gustavo C. Rodriguez, Trinidad Caldes, Miguel de La Hoya, Sofia Khan, Frans B. L. Hogervorst, Cora M. Aalfs, J. L. de Lange, Hanne E. J. Meijers-Heijboer, Annemarie H. van der Hout, Juul T. Wijnen, K. E. P. van Roozendaal, Arjen R. Mensenkamp, Ans M. W. van den Ouweland, Carolien H. M. van Deurzen, Rob B. van der Luijt, Edith Olah, Orland Diez, Conxi Lazaro, Ignacio Blanco, Alex Teulé, Mireia Menendez, Anna Jakubowska, Jan Lubinski, Cezary Cybulski, Jacek Gronwald, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Adalgeir Arason, Christine Maugard, Penny Soucy, Marco Montagna, Simona Agata, Manuel R. Teixeira, Curtis Olswold, Noralane Lindor, Vernon S. Pankratz, Emily Hallberg, Xianshu Wang, Csilla I. Szabo, Joseph Vijai, Lauren Jacobs, Marina Corines, Anne Lincoln, Andreas Berger, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Gschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Catherine M. Phelan, Phuong L. Mai, Mark H. Greene, Gad Rennert, Evgeny N. Imyanitov, Gord Glendon, Amanda Ewart Toland, Anders Bojesen, Inge Sokilde Pedersen, Uffe Birk Jensen, Maria A. Caligo, Eitan Friedman, Raanan Berger, Yael Laitman, Johanna Rantala, Brita Arver, Niklas Loman, Ake Borg, Hans Ehrencrona, Olufunmilayo I. Olopade, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench, Kenneth Offit, Fergus J. Couch, Antonis C. Antoniou

Date Published: 1st Dec 2014

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Associations of Sex Hormones and Anthropometry with the Speaking Voice Profile in the Adult General Population.
LIFE Adult

Abstract (Expand)

OBJECTIVE: There is evidence that sexual hormone concentrations and anthropometric factors influence the human voice. The goal of this study was to investigate to what extent body mass index (BMI), … body height, body weight, breast-to-abdomen-ratio, testosterone, estradiol, dehydroepiandrosterone-sulfate (DHEA-S), follicle-stimulating hormone, and luteinizing hormone are associated with the sound pressure level and the fundamental frequency of the speaking voice in a cross-sectional approach among adults in the general population. METHODS: Speaking voice profiles with four different intensity levels, hormone concentrations, and anthropometric parameters were assessed for 2,381 individuals aged 40-79 years, who were randomly sampled from the population of a large city in Germany. Multivariate analysis was performed, adjusting for age and stratified by sex. RESULTS: Taller body height was associated with lower frequencies. Higher body weight was associated with lower frequencies and higher sound pressure levels. The ratio of chest to abdominal circumference was associated with the sound pressure levels in males and females: participants with larger breast-to-abdomen-ratio were found to have higher sound pressure levels. Among the sexual hormones, higher concentrations of DHEA-S were associated with lower fundamental frequencies of the voice while using the normal speaking voice. In addition, bioavailable testosterone was associated with the sound pressure level of the normal speaking voice in men and the softest speaking voice in women. CONCLUSION: Our findings suggest that BMI, body height, body weight, breast-to-abdomen-ratio, bioavailable testosterone, and DHEA-S are associated with the speaking voice in adults. No associations between testosterone and the frequency of the speaking voice were found.

Authors: L. Jost, M. Fuchs, M. Loeffler, J. Thiery, J. Kratzsch, T. Berger, C. Engel

Date Published: 26th Jul 2017

Publication Type: Journal article

Atopic dermatitis is associated with autoimmune but not with cardiovascular comorbidities in a random sample of the general population in Leipzig, Germany.
LIFE Adult

Abstract

Not specified

Authors: R. Treudler, S. Zeynalova, F. Walther, C. Engel, J. C. Simon

Date Published: 2nd Aug 2017

Publication Type: Journal article

Human Diseases: atopic dermatitis

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

Atrophy and structural covariance of the cholinergic basal forebrain in primary progressive aphasia.
LIFE Adult

Abstract (Expand)

Primary progressive aphasia (PPA) is characterized by profound destruction of cortical language areas. Anatomical studies suggest an involvement of cholinergic basal forebrain (BF) in PPA syndromes, … particularly in the area of the nucleus subputaminalis (NSP). Here we aimed to determine the pattern of atrophy and structural covariance as a proxy of structural connectivity of BF nuclei in PPA variants. We studied 62 prospectively recruited cases with the clinical diagnosis of PPA and 31 healthy older control participants from the cohort study of the German consortium for frontotemporal lobar degeneration (FTLD). We determined cortical and BF atrophy based on high-resolution magnetic resonance imaging (MRI) scans. Patterns of structural covariance of BF with cortical regions were determined using voxel-based partial least square analysis. We found significant atrophy of total BF and BF subregions in PPA patients compared with controls [F(1, 82) = 20.2, p < .001]. Atrophy was most pronounced in the NSP and the posterior BF, and most severe in the semantic variant and the nonfluent variant of PPA. Structural covariance analysis in healthy controls revealed associations of the BF nuclei, particularly the NSP, with left hemispheric predominant prefrontal, lateral temporal, and parietal cortical areas, including Broca's speech area (p < .001, permutation test). In contrast, the PPA patients showed preserved structural covariance of the BF nuclei mostly with right but not with left hemispheric cortical areas (p < .001, permutation test). Our findings agree with the neuroanatomically proposed involvement of the cholinergic BF, particularly the NSP, in PPA syndromes. We found a shift from a structural covariance of the BF with left hemispheric cortical areas in healthy aging towards right hemispheric cortical areas in PPA, possibly reflecting a consequence of the profound and early destruction of cortical language areas in PPA.

Authors: S. Teipel, T. Raiser, L. Riedl, I. Riederer, M. L. Schroeter, S. Bisenius, A. Schneider, J. Kornhuber, K. Fliessbach, A. Spottke, M. J. Grothe, J. Prudlo, J. Kassubek, A. Ludolph, B. Landwehrmeyer, S. Straub, M. Otto, A. Danek

Date Published: 11th Aug 2016

Publication Type: Journal article

Human Diseases: aphasia

AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a consortium of investigators of modifiers of BRCA1/2 study
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and … BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers.

Authors: Fergus J. Couch, Olga Sinilnikova, Robert A. Vierkant, V. Shane Pankratz, Zachary S. Fredericksen, Dominique Stoppa-Lyonnet, Isabelle Coupier, David Hughes, Agnès Hardouin, Pascaline Berthet, Susan Peock, Margaret Cook, Caroline Baynes, Shirley Hodgson, Patrick J. Morrison, Mary E. Porteous, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Amanda B. Spurdle, Rita Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Christian Sutter, Jurgen Horst, Dieter Schaefer, Kenneth Offit, Tomas Kirchhoff, Irene L. Andrulis, Eduard Ilyushik, Gordon Glendon, Peter Devilee, Maaike P. G. Vreeswijk, Hans F. A. Vasen, Ake Borg, Katja Backenhorn, Jeffery P. Struewing, Mark H. Greene, Susan L. Neuhausen, Timothy R. Rebbeck, Katherine Nathanson, Susan Domchek, Theresa Wagner, Judy E. Garber, Csilla Szabo, Michal Zikan, Lenka Foretova, Janet E. Olson, Thomas A. Sellers, Noralane Lindor, Heli Nevanlinna, Johanna Tommiska, Kristiina Aittomaki, Ute Hamann, Muhammad U. Rashid, Diana Torres, Jacques Simard, Francine Durocher, Frederic Guenard, Henry T. Lynch, Claudine Isaacs, Jeffrey Weitzel, Olufunmilayo I. Olopade, Steven Narod, Mary B. Daly, Andrew K. Godwin, Gail Tomlinson, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou

Date Published: 1st Jul 2007

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Automated detection of the choroid boundary within OCT image data using quadratic measure filters.
LIFE Child

Abstract (Expand)

A novel method for the automated detection of the outer choroid boundary within spectral-domain optical coherence tomography image data, based on an image model within the space of functions of bounded … variation and the application of quadratic measure filters, is presented. The same method is used for the segmentation of retinal layer boundaries and proves to be suitable even for data generated without special imaging modes and moderate line averaging. Based on the segmentations, an automated determination of the central fovea region and choroidal thickness measurements for this and two adjacent 1-mm regions are provided. The quality of the method is assessed by comparison with manual delineations performed by five trained graders. The study is based on data from 50 children of the ages 8 to 13 that were obtained in the framework of the LIFE Child study at Leipzig University.

Authors: M. Wagner, P. Scheibe, M. Francke, B. Zimmerling, K. Frey, M. Vogel, S. Luckhaus, P. Wiedemann, W. Kiess, F. G. Rauscher

Date Published: 1st Feb 2017

Publication Type: Journal article

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