Markus Loeffler

University of Leipzig, Leipzig, Saxony, Germany

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Publications (361)2044.95 Total impact

  • A Dietz · M Loeffler · M Rosolowski · M Kreuz · F Lordick · M Knödler · C Mozet · G Wichmann ·
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    ABSTRACT: Systems biology approaches for mutational (exome analysis and targeted sequencing) and gene expression analysis (transcriptome-wide gene expression profiling) represent a new and growing scientific field in head and neck oncology. In addition to medical biological expertise, bioinformatic assistance is increasingly required. For squamous cell head and neck cancer (HNSCC), the recent molecular genetic single-gene and signal pathway observations represent basic research. Important aspects of this have now been significantly enhanced by systems biology approaches, which have grown into relevant areas of translational clinical research. It is now known that HPV16 is associated with genetic alterations at various locations, but also that it functionally affects genes not altered in their base sequence at the level of methylation. In transcriptome analyses, various consortia found matching clusters of gene expression and HPV16 association with the spectrum of somatic mutations. The differential methylation of gene promoters discovered in HPV16-driven HNSCC proved predictive for survival-even in HNSCC patients without HPV detection. The authors present an overview of some translationally relevant findings and venture an outlook on possible future clinical developments.
    HNO 10/2015; DOI:10.1007/s00106-015-0078-6 · 0.58 Impact Factor
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    ABSTRACT: Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas.
    Nature Genetics 10/2015; DOI:10.1038/ng.3413 · 29.35 Impact Factor
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    ABSTRACT: Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.
    Proceedings of the National Academy of Sciences 09/2015; 112(38). DOI:10.1073/pnas.1505753112 · 9.67 Impact Factor
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    ABSTRACT: The Three-Factor-Eating-Questionnaire (TFEQ) is an established instrument to assess eating behaviour. Analysis of the TFEQ-factor structure was based on selected, convenient and clinical samples so far. Aims of this study were (I) to analyse the factor structure of the German version of the TFEQ and (II)-based on the refined factor structure-to examine the association between eating behaviour and the body mass index (BMI) in a general population sample of 3,144 middle-aged and older participants (40-79 years) of the ongoing population based cohort study of the Leipzig Research Center for Civilization Diseases (LIFE Health Study). The factor structure was examined in a split-half analysis with both explorative and confirmatory factor analysis. Associations between TFEQ-scores and BMI values were tested with multiple regression analyses controlled for age, gender, and education. We found a three factor solution for the TFEQ with an 'uncontrolled eating', a 'cognitive restraint' and an 'emotional eating' domain including 29 of the original 51 TFEQ-items. Scores of the 'uncontrolled eating domain' showed the strongest correlation with BMI values (partial r = 0.26). Subjects with scores above the median in both 'uncontrolled eating' and 'emotional eating' showed the highest BMI values (mean = 29.41 kg/m²), subjects with scores below the median in all three domains showed the lowest BMI values (mean = 25.68 kg/m²; F = 72.074, p<0.001). Our findings suggest that the TFEQ is suitable to identify subjects with specific patterns of eating behaviour that are associated with higher BMI values. Such information may help health care professionals to develop and implement more tailored interventions for overweight and obese individuals.
    PLoS ONE 07/2015; 10(7). DOI:10.1371/journal.pone.0133977 · 3.23 Impact Factor
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    ABSTRACT: Background The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies. Methods/design The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography. Discussion The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.
    BMC Public Health 07/2015; 15(1). DOI:10.1186/s12889-015-1983-z · 2.26 Impact Factor
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    ABSTRACT: The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG-MYC juxtaposition. However, these translocations alone are insufficient to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole-genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron-less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K-Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre-mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20-40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 07/2015; 54(9). DOI:10.1002/gcc.22268 · 4.04 Impact Factor
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    ABSTRACT: Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC. This article is protected by copyright. All rights reserved. © 2015 UICC.
    International Journal of Cancer 06/2015; 137(12). DOI:10.1002/ijc.29649 · 5.09 Impact Factor
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    ABSTRACT: Genetics of gene expression (eQTLs or expression QTLs) has proved an indispensable tool for understanding biological pathways and pathomechanisms of trait associated SNPs. However, power of most genome-wide eQTL studies is still limited. We performed a large eQTL study in peripheral blood mononuclear cells of 2,112 individuals increasing the power to detect trans-effects genome-wide. Going beyond univariate SNP-transcript associations, we analyse relations of eQTLs to biological pathways, polygenetic effects of expression regulation, trans-clusters, and enrichment of co-localised functional elements. We found eQTLs for about 85% of analysed genes, 18% of genes were trans-regulated. Local eSNPs were enriched up to a distance of 5 Mb to the transcript challenging typically implemented ranges of cis-regulations. Pathway enrichment within regulated genes of GWAS-related eSNPs supported functional relevance of identified eQTLs. We demonstrate that nearest genes of GWAS-SNPs might frequently be misleading functional candidates. We identified novel trans-clusters of potential functional relevance for GWAS-SNPs of several phenotypes including obesity-related traits, HDL-cholesterol levels, and haematological phenotypes. We used chromatin immunoprecipitation data for demonstrating biological effects. Yet, we show for strongly heritable transcripts that still little trans-chromosomal heritability is explained by all identified trans-eSNPs, however, our data suggests that most cis-heritability of these transcripts seems explained. Dissection of co-localised functional elements indicated a prominent role of SNPs in loci of pseudogenes and non-coding RNAs for the regulation of coding genes. In summary, our study substantially increases the catalogue of human eQTLs and improves our understanding of the complex genetic regulation of gene-expression, pathways and disease-related processes. © The Author 2015. Published by Oxford University Press.
    Human Molecular Genetics 05/2015; 24(16). DOI:10.1093/hmg/ddv194 · 6.39 Impact Factor
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    ABSTRACT: 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. 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. 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. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Gut 04/2015; DOI:10.1136/gutjnl-2014-309026 · 14.66 Impact Factor
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    ABSTRACT: 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 3,144 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 programs for overweight, obesity, and eating disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Appetite 04/2015; 91. DOI:10.1016/j.appet.2015.04.044 · 2.69 Impact Factor
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    ABSTRACT: Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.
    Acta Neuropathologica 03/2015; 129(5). DOI:10.1007/s00401-015-1409-0 · 10.76 Impact Factor
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    ABSTRACT: Background Reference intervals for leukocyte subsets from peripheral blood are helpful for the understanding of disease states and therapy effects. Methods We performed in-depth immunophenotyping for 608 healthy German adults from the Leipzig region from 40 to 79 years by 10-color flow cytometry (FCM) to gain reference information for various leukocyte subsets including subsets of granulocytes, monocytes and lymphocytes. Results First, we derived gender- and age-specific reference intervals for males and females from 40 to 59 and from 60 to 79 years, respectively. Second, we further investigated the influence of gender and age on leukocyte counts. We found significantly higher cell counts for monocytes (p<.001) and NK cells (p<.001) in men, whereas women had higher counts for B cells (p<.001), Th cells (p<.001) and regulatory T cells (p=.008). Furthermore, with increasing age, a decrease in Tc cells (about 8% within five years) and an increase in NK cells (less than 4% within five years) were observed. Conclusion In future research, it should be investigated whether these are real ageing effects that can be confirmed in longitudinal studies. Furthermore, it is important to understand if the Tc cell count drop is functionally compensated by the increase of NK cells. This article is protected by copyright. All rights reserved. Copyright © 2015 Clinical Cytometry Society.
    Cytometry Part B Clinical Cytometry 02/2015; 88(4). DOI:10.1002/cyto.b.21234 · 2.40 Impact Factor
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    ABSTRACT: Prognostically-relevant risk factors in patients with diffuse large B-cell lymphoma (DLBCL) have predominantly been evaluated in elderly populations. We tested whether previously described risk factors are also valid in younger, poor-prognosis DLBCL patients. Paraffin-embedded samples from 112 patients with de novo DLBCL, enrolled in the R-MegaCHOEP trial of the German High Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry (MYC, FOXP1, LMO2, GCET1, CD5, CD10, BCL2, BCL6, IRF4/MUM1) and fluorescence in situ hybridization (MYC, BCL2, BCL6). MYC, BCL2 and BCL6 breaks occurred in 14%, 21% and 31%, respectively. In the majority of cases, MYC was simultaneously rearranged with BCL2 and/or BCL6. The adverse impact of MYC rearrangements was confirmed, but the sole presence of BCL2 breaks emerged as a novel prognostic marker associated with inferior overall survival (OS) (p=0.002). Combined over-expression of MYC and BCL2 showed only limited association with inferior OS. All immunohistochemical cell of origin (COO) classifiers applied failed to predict survival time. DLBCL tumors with significant proportion of immunoblastic and/or immunoblastic-plasmacytoid cells had inferior OS, independently from from BCL2 break. Younger, poor-prognosis DLBCL patients, therefore, display different biological risk factors compared to an elderly population, with BCL2 translocations emerging as a powerful negative prognostic marker.Leukemia accepted article preview online, 17 February 2015. doi:10.1038/leu.2015.43.
    Leukemia 02/2015; 29(7). DOI:10.1038/leu.2015.43 · 10.43 Impact Factor
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    Sibylle Schirm · Christoph Engel · Markus Loeffler · Markus Scholz ·
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    ABSTRACT: Background Although the growth-factor G-CSF is widely used to prevent granulotoxic side effects of cytotoxic chemotherapies, its optimal use is still unknown since treatment outcome depends on many parameters such as dosing and timing of chemotherapies, pharmaceutical derivative of G-CSF used and individual risk factors. We showed in the past that a pharmacokinetic and ¿dynamic model of G-CSF and human granulopoiesis can be used to predict the performance of yet untested G-CSF schedules. However, only a single chemotherapy was considered so far.In the present paper, we propose a comprehensive model of chemotherapy toxicity and combine it with our cell kinetic model of granulopoiesis. Major assumptions are: proportionality of cell numbers and cell loss, delayed action of chemotherapy, drug, drug-dose and cell stage specific toxicities, no interaction of drugs and higher toxicity of drugs at the first time of application. Correspondingly, chemotherapies can be characterized by a set of toxicity parameters which can be estimated by fitting the predictions of our model to clinical time series data of patients under therapy. Data were either extracted from the literature or were received from cooperating clinical study groups.ResultsModel assumptions proved to be feasible in explaining granulotoxicity of 10 different chemotherapeutic drugs or drug-combinations applied in 33 different schedules with and without G-CSF. Risk groups of granulotoxicity were traced back to differences in toxicity parameters.Conclusion We established a comprehensive model of combined G-CSF and chemotherapy action in humans which allows us to predict and compare the outcome of alternative G-CSF schedules. We aim to apply the model in different clinical contexts to optimize and individualize G-CSF treatment.
    BMC Systems Biology 12/2014; 8(1):5. DOI:10.1186/s12918-014-0138-7 · 2.44 Impact Factor
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    ABSTRACT: Objective: To test for a possible effect of the apolipoprotein E epsilon 4 (APOE ε4) 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 ε4 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 ε4 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 ε4 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.
    Neuropsychology 11/2014; 29(3). DOI:10.1037/neu0000147 · 3.27 Impact Factor
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    ABSTRACT: The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. To elucidate the molecular aberrations in glioblastomas of long-term survivors, we performed genome- and/or transcriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-term survivors with >36 months overall survival (OS), 20 short-term survivors with <12 months OS, and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups of IDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomas in our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 10/2014; 135(8). DOI:10.1002/ijc.28836 · 5.09 Impact Factor
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    ABSTRACT: Follicular lymphoma (FL) with a t(14;18) is a B-cell neoplasm clinically characterized by multiple recurrencies. In order to investigate the clonal evolution of this lymphoma we studied paired primary and relapse tumor samples from 33 patients with recurrent non-transformed t(14;18)-positive FL. We reconstruct phylogenetic trees of the evolution by taking advantage of the AID-mediated somatic hypermutation (SHM) active in the germinal center reaction using sequences of the clonal VHDHJH rearrangements of the immunoglobulin heavy chain (IGH) locus. Mutational analysis of the IGH locus showed evidence for ongoing somatic mutation and for counter-selection of mutations affecting the BCR conformation during tumor evolution. We further followed evolutionary divergence by targeted sequencing of gene loci affected by aberrant SHM as well as of known driver genes of lymphomagenesis, and by array based genome-wide chromosomal imbalance and DNA methylation analysis. We observed a wide spectrum of evolutionary patterns ranging from almost no evolution to divergent evolution within recurrent non-transformed t(14;18) FL. Remarkably, we observed a correlation of the magnitude of evolutionary divergence across all genetic and epigenetic levels suggesting co-evolution. The distribution of coding mutations in driver genes and the correlation with SHM suggest CREBBP and AID to be potential modifiers of genetic and epigenetic co-evolution in FL.Leukemia accepted article preview online, 16 July 2014; doi:10.1038/leu.2014.209.
    Leukemia 07/2014; 29(2). DOI:10.1038/leu.2014.209 · 10.43 Impact Factor
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    ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    Leukemia 07/2014; 28(11). DOI:10.1038/leu.2014.213 · 10.43 Impact Factor
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    ABSTRACT: The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. We aimed to elucidate the poorly characterized molecular aberrations in glioblastomas of longterm survivors.
    Neuro-Oncology 07/2014; 16 Suppl 3:iii46-iii47. DOI:10.1093/neuonc/nou209.19 · 5.56 Impact Factor

Publication Stats

16k Citations
2,044.95 Total Impact Points


  • 1995-2015
    • University of Leipzig
      • Institute of Medical Informatics, Statistics and Epidemiology
      Leipzig, Saxony, Germany
  • 2014
    • University of Zurich
      • Division of Neuropsychology
      Zürich, Zurich, Switzerland
  • 2012
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 2011
    • University of Wuerzburg
      • Institute for Psychotherapy and Medical Psychology
      Würzburg, Bavaria, Germany
  • 2009
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1985-2009
    • University of Cologne
      • • Division of Haematology, Immunology, Infectiology, Intensive Care and Oncology
      • • Division of Cardiology, Pneumology, Angiology and Intensive Care
      • • Department of Internal Medicine
      • • Institute of Medical Statistics, Epidemiology and Computer Science
      Köln, North Rhine-Westphalia, Germany
  • 2008
    • McMaster University
      Hamilton, Ontario, Canada
  • 2005-2008
    • Friedrich-Schiller-University Jena
      • Department of Anaesthesiology and Intensive Care Medicine
      Jena, Thuringia, Germany
    • Max Planck Institute for Mathematics in the Sciences
      Leipzig, Saxony, Germany
  • 2006
    • Universitätsmedizin Göttingen
      • Department of Hematology and Oncology
      Göttingen, Lower Saxony, Germany
  • 1998-2000
    • Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V.
      Leipzig, Saxony, Germany
  • 1990
    • Bergische Universität Wuppertal
      Wuppertal, North Rhine-Westphalia, Germany
  • 1989-1990
    • University of Groningen
      Groningen, Groningen, Netherlands