Publications by authors named "Maciej Rosolowski"

26 Publications

  • Page 1 of 1

The novel cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide (CLIP)-based mortality risk score in cardiogenic shock after acute myocardial infarction.

Eur Heart J 2021 06;42(24):2344-2352

Heart Center Leipzig at University of Leipzig, Department of Internal Medicine/Cardiology, Strümpellstr.. 39, 04289 Leipzig, and Leipzig Heart Institute, Leipzig, Germany.

Background: Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) still reaches excessively high mortality rates. This analysis is aimed to develop a new easily applicable biomarker-based risk score.

Methods And Results: A biomarker-based risk score for 30-day mortality was developed from 458 patients with CS complicating AMI included in the randomized CULPRIT-SHOCK trial. The selection of relevant predictors and the coefficient estimation for the prognostic model were performed by a penalized multivariate logistic regression analysis. Validation was performed internally, internally externally as well as externally in 163 patients with CS included in the randomized IABP-SHOCK II trial. Blood samples were obtained at randomization. The two trials are registered with ClinicalTrials.gov (NCT01927549 and NCT00491036), are closed to new participants, and follow-up is completed. Out of 58 candidate variables, the four strongest predictors for 30-day mortality were included in the CLIP score (cystatin C, lactate, interleukin-6, and N-terminal pro-B-type natriuretic peptide). The score was well calibrated and yielded high c-statistics of 0.82 [95% confidence interval (CI) 0.78-0.86] in internal validation, 0.82 (95% CI 0.75-0.89) in internal-external (temporal) validation, and 0.73 (95% CI 0.65-0.81) in external validation. Notably, it outperformed the Simplified Acute Physiology Score II and IABP-SHOCK II risk score in prognostication (0.83 vs 0.62; P < 0.001 and 0.83 vs. 0.76; P = 0.03, respectively).

Conclusions: A biomarker-only score for 30-day mortality risk stratification in infarct-related CS was developed, extensively validated and calibrated in a prospective cohort of contemporary patients with CS after AMI. The CLIP score outperformed other clinical scores and may be useful as an early decision tool in CS.
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http://dx.doi.org/10.1093/eurheartj/ehab110DOI Listing
June 2021

VEGFR2 and VEGFA polymorphisms are not associated with an inferior prognosis in Caucasian patients with aggressive B-cell lymphoma.

Eur J Haematol 2021 Jan 22;106(1):100-104. Epub 2020 Oct 22.

Department of Hematology and Oncology, Saarland University Medical School, Homburg, Germany.

Purpose: Previous published data showed an impact of single-nucleotide polymorphisms in the VEGF A and VEGFR2 genes on the survival of patients with various malignancies, among others diffuse large B-cell lymphoma (DLBCL).

Patients And Methods: We investigated the role of four VEGF-A and two VEGFR-2 gene polymorphisms on the outcome of 273 patients with diffuse large B-cell lymphoma who were treated with R-CHOP within a prospective, randomized trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). The genomic DNA samples were analyzed using commercial DNA Probes (Applied Biosystems, USA) to detect single-nucleotide polymorphisms in the VEGF A rs699947, rs1570360, rs2010963, rs3025039 and rs1870377, and rs2305948 in the VEGFR2 receptor. Hundred healthy blood donors served as a control.

Results: There was no difference between the SNP allele frequencies in lymphoma patients compared to the control group for all investigated SNPs. None of the investigated SNPs was significantly associated with EFS or OS. After adjusting for the International Prognostic Index risk factors in a multivariate analysis, these results could be confirmed.

Conclusion: Single-nucleotide polymorphisms of the VEGF and VEGFR2 were not associated with a worse outcome in Caucasian patients with DLBCL.
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http://dx.doi.org/10.1111/ejh.13526DOI Listing
January 2021

Dynamics of cytokines, immune cell counts and disease severity in patients with community-acquired pneumonia - Unravelling potential causal relationships.

Cytokine 2020 12 4;136:155263. Epub 2020 Sep 4.

Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Background: Community acquired pneumonia (CAP) is a severe and often rapidly deteriorating disease. To better understand its dynamics and potential causal relationships, we analyzed time series data of cytokines, blood and clinical parameters in hospitalized CAP patients.

Methods: Time series data of 10 circulating cytokines, blood counts and clinical parameters were related to baseline characteristics of 403 CAP patients using univariate mixed models. Bivariate mixed models were applied to analyze correlations between the time series. To identify potential causal relationships, we inferred cross-lagged relationships between pairs of parameters using latent curve models with structured residuals.

Results: IL-6 levels decreased faster over time in younger patients (P = 0.06). IL-8, VCAM-1, and IL-6 correlated strongly with disease severity as assessed by the sequential organ failure assessment (SOFA) score (r = 0.49, 0.48, 0.46, respectively; all P < 0.001). IL-6 and bilirubin correlated with respect to their mean levels and slopes over time (r = 0.36 and r = 0.46, respectively; P < 0.001). A number of potential causal relationships were identified, e.g., a negative effect of ICAM-1 on MCP-1, or a positive effect of the level of creatinine on the subsequent VCAM-1 concentration (P < 0.001).

Conclusions: These results suggest that IL-6 trajectories of CAP patients are associated with age and run parallel to bilirubin levels. The time series analysis also unraveled directed, potentially causal relationships between cytokines, blood parameters and clinical outcomes. This will facilitate the development of mechanistic models of CAP, and with it, improvements in treatment or surveillance strategies for this disease.

Trial Registration: clinicaltrials.gov NCT02782013, May 25, 2016, retrospectively registered.
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http://dx.doi.org/10.1016/j.cyto.2020.155263DOI Listing
December 2020

Borderline resistance to oxacillin in after treatment with sub-lethal sodium hypochlorite concentrations.

Heliyon 2020 Jun 21;6(6):e04070. Epub 2020 Jun 21.

Institute of Animal Hygiene and Veterinary Public Health, University of Leipzig, Leipzig, Germany.

Surface disinfectants are regularly used in prophylactic and infection control measures. Concern has been raised whether residues of sub-inhibitory disinfectant concentrations may constitute a selective pressure and could contribute to the development of strains which are tolerant and/or resistant to biocides including antibiotics. The current study investigated whether (.) ATCC® 29213™ and ATCC® 6538™ would change their growth characteristics and antimicrobial susceptibility profiles after prolonged treatment with sub-inhibitory concentrations of sodium hypochlorite (NaOCl). NaOCl is a fast-acting disinfectant with a broad-spectrum activity, inexpensive and widely used in healthcare and the food production industry. Minimum inhibitory concentration (MIC) for NaOCl was determined by broth macrodilution according to the guidelines for disinfectant efficacy testing provided by the German Veterinary Medical Society. Serial passages after 24 h and 72 h, respectively, in defined sub-inhibitory concentrations of NaOCl resulted in a number of phenotypic variants. Two of these variants, derived from . ATCC® 29213™, showed elevated MICs of oxacillin and were considered as generated borderline oxacillin-resistant (BORSA). Transmission electron microscopy revealed a significantly thickened cell wall in these isolates, a phenomenon that has also been described for after low-level exposure to NaOCl. Whole genome sequencing revealed an early stop codon in the gene coding for the GdpP protein and thereby abolishing the function of this gene. GdpP represents a phosphodiesterase that regulates gene expression, and loss of function of the GdpP protein has been described in association with borderline oxacillin resistance. Our findings suggest that a mutation in the GdpP protein gene and morphological changes of the cell wall were induced by repeated exposure to sub-lethal NaOCl concentrations, and most likely accounted for a BORSA phenotype in two variants derived from ATCC® 29213™.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317233PMC
June 2020

Association of proteome and metabolome signatures with severity in patients with community-acquired pneumonia.

J Proteomics 2020 03 30;214:103627. Epub 2019 Dec 30.

Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Str. 8, 17475 Greifswald, Germany. Electronic address:

A combined OMICS screening approach of human plasma and serum was used to characterize protein and metabolome signatures displaying association to severity of Community-acquired pneumonia (CAP). 240 serum and BD P100 EDTA plasma samples from patients diagnosed with CAP, collected during the day of enrolment to the hospital, were analyzed by a metabolomic and proteomic approach, respectively. Disease severity of CAP patients was stratified using the Sequential Organ Failure Assessment (SOFA) score. Quantitative proteome and metabolome data, derived by LC-MS/MS, were associated to SOFA and specific parameters of SOFA using linear regression models adjusted for age, BMI, sex, smoking and technical variables. Both proteome and metabolome profiling revealed remarkable strong changes in plasma and serum composition in relation to severity of CAP. Proteins and metabolites displaying SOFA associated levels are involved in immune response, particularly in processes of lipid metabolism. Proteins, which show an association to SOFA score, are involved in acute phase response, coagulation, complement activation and inflammation. Many of these metabolites and proteins displayed not only associations to SOFA, but also to parameters of SOFA score, which likely reflect the strong influence of lung-, liver-, kidney- and heart-dysfunction on the metabolome and proteome patterns. SIGNIFICANCE: Community-acquired pneumonia is the most frequent infection disease with high morbidity and mortality. So far, only few studies focused on the identification of proteins or metabolites associated to severity of CAP, often based on smaller sample sets. A screening for new diagnostic markers requires extensive sample collections in combination with high quality clinical data. To characterize the proteomic and metabolomics pattern associated to severity of CAP we performed a combined metabolomics and proteomic approach of serum and plasma sample from a multi-center clinical study focused on patients with CAP, requiring hospitalization. The results of this association study of omics data to the SOFA score enable not only an interpretation of changes in molecular patterns with severity of CAP but also an assignment of altered molecules to dysfunctions of respiratory, renal, coagulation, cardiovascular systems as well as liver.
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http://dx.doi.org/10.1016/j.jprot.2019.103627DOI Listing
March 2020

Clinical and OCT outcomes of a universal adhesive in a randomized clinical trial after 12 months.

J Dent 2019 11 25;90:103200. Epub 2019 Sep 25.

Department of Cariology, Endodontology and Periodontology, University of Leipzig, Liebigstraße 12, 04103 Leipzig, Germany. Electronic address:

Objectives: To assess the performance of a universal adhesive in different application modes in non-carious cervical lesions clinically and by optical coherence tomography (OCT).

Methods: 55 adult patients with three non-carious cervical lesions (NCCL) each participated in the study. Lesions were restored with Scotchbond™ Universal (SBU, 3 M) applied in the self-etch (SBU-SE) and the selective-enamel-etch mode (SBU-SEE) in combination with Filtek™ Supreme XTE (3 M). OptiBond™ FL (OFL, Kerr) was used as a control. Restorations were clinically assessed (FDI criteria) after 14 days, 6 and 12 months and in parallel imaged by OCT (interfacial adhesive defects), starting immediately after filling placement. Cumulative failure rates (CFR) and means of interfacial adhesive defect were statistically evaluated.

Results: After 12 months, CFRs were lower in the SBU groups (0.0% each) than in the OFL group (20.0%, p = 0.001). Clinically, small marginal fractures occurred three times more often in the SBU-SE than in the SBU-SEE group (p = 0.001). Immediately after filling placement and at each reassessment OCT revealed more interfacial defects at enamel interfaces for SBU/SE compared to SBU/SEE and OFL (p ≤ 0.044). At dentin/cement more defects were seen with OFL compared to SBU/SE and SBU/SEE (p ≤ 0.001). Before restoration loss, more interfacial defects appeared compared to remaining restorations (p = 0.132/0.002).

Conclusions: Clinical evaluation and OCT imaging revealed higher interfacial integrity for SBU in both application modes compared to OFL. OCT detected interfacial bond failures prior to clinical deterioration or restoration loss.

Clinical Significance: Scotchbond Universal showed an equivalent or improved bonding performance compared to the reference adhesive. Selective enamel etching is recommended. The parameter interfacial adhesive defect seems to be a valuable predictor for evaluation of adhesive restoration systems.
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http://dx.doi.org/10.1016/j.jdent.2019.103200DOI Listing
November 2019

Early Prognostication after Traumatic Brain Injury: Specific Validation of the IMPACT Prognostic Calculator in a Level 1 Trauma Center.

J Neurol Surg A Cent Eur Neurosurg 2019 Nov 20;80(6):423-429. Epub 2019 Aug 20.

Department of Neurosurgery, University Hospital Leipzig, Leipzig, Germany.

The present study evaluated the usefulness of the IMPACT prognostic calculator (IPC) for patients receiving acute neurointensive care at a level 1 trauma center in Germany. A total of 139 patients with traumatic brain injury (TBI) were assessed. One day after trauma, the extended model of the IPC was found to provide the most valid prediction of 6-month mortality/unfavorable outcome. Different time frames within the first day could be determined by analyzing mild, moderate, and severe TBI cohorts. The CORE + CT model at time frame Z2 (<6 h from the point of first documentation) for mild TBI exhibited the highest values in the receiver operating characteristic (ROC) analysis (area under the curve [AUC], 0.9; sensitivity, 1; specificity, 0.7). For patients with moderate head injury at time frame Z2/3 (<6-12 h from point of first documentation), the extended model fit best. For patients with severe TBI, the extended model at time frame Z6 (48-72 h from point of first documentation) best predicted 6-month mortality and unfavorable outcome (ROC analysis: AUC, 0.542/0.445; sensitivity, 0.167/0.364; specificity, 0.575/0.444). Center-specific validation demonstrated the validity of the IPC in the early phase after TBI. These findings support the usefulness of the IPC for predicting the prognosis of patients with TBI. However, further prospective validation using a larger TBI cohort is needed.
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http://dx.doi.org/10.1055/s-0039-1685137DOI Listing
November 2019

MDM4 Is Targeted by 1q Gain and Drives Disease in Burkitt Lymphoma.

Cancer Res 2019 06 18;79(12):3125-3138. Epub 2019 Apr 18.

III. Medical Department of Hematology and Medical Oncology, Technical University of Munich, Germany.

Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases. To identify molecular dependencies in Burkitt lymphoma, we performed RNAi-based, loss-of-function screening in eight Burkitt lymphoma cell lines and integrated non-Burkitt lymphoma RNAi screens and genetic data. We identified 76 genes essential to Burkitt lymphoma, including genes associated with hematopoietic cell differentiation () or B-cell development and activation () and found a number of context-specific dependencies including oncogene addiction in cell lines with / or mutation. The strongest genotype-phenotype association was seen for . MDM4, a negative regulator of , was essential in wild-type (TP53wt) Burkitt lymphoma cell lines. knockdown activated p53, induced cell-cycle arrest, and decreased tumor growth in a xenograft model in a p53-dependent manner. Small molecule inhibition of the MDM4-p53 interaction was effective only in TP53wt Burkitt lymphoma cell lines. Moreover, primary TP53wt Burkitt lymphoma samples frequently acquired gains of chromosome 1q, which includes the locus, and showed elevated MDM4 mRNA levels. 1q gain was associated with TP53wt across 789 cancer cell lines and was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles Project. Our findings highlight the critical role of p53 as a tumor suppressor in Burkitt lymphoma and identify MDM4 as a functional target of 1q gain in a wide range of cancers that is therapeutically targetable. SIGNIFICANCE: Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3438DOI Listing
June 2019

Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome.

J Pathol 2017 10 5;243(2):242-254. Epub 2017 Sep 5.

Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.

Colorectal cancer (CRC) arising in Lynch syndrome (LS) comprises tumours with constitutional mutations in DNA mismatch repair genes. There is still a lack of whole-genome and transcriptome studies of LS-CRC to address questions about similarities and differences in mutation and gene expression characteristics between LS-CRC and sporadic CRC, about the molecular heterogeneity of LS-CRC, and about specific mechanisms of LS-CRC genesis linked to dysfunctional mismatch repair in LS colonic mucosa and the possible role of immune editing. Here, we provide a first molecular characterization of LS tumours and of matched tumour-distant reference colonic mucosa based on whole-genome DNA-sequencing and RNA-sequencing analyses. Our data support two subgroups of LS-CRCs, G1 and G2, whereby G1 tumours show a higher number of somatic mutations, a higher amount of microsatellite slippage, and a different mutation spectrum. The gene expression phenotypes support this difference. Reference mucosa of G1 shows a strong immune response associated with the expression of HLA and immune checkpoint genes and the invasion of CD4+ T cells. Such an immune response is not observed in LS tumours, G2 reference and normal (non-Lynch) mucosa, and sporadic CRC. We hypothesize that G1 tumours are edited for escape from a highly immunogenic microenvironment via loss of HLA presentation and T-cell exhaustion. In contrast, G2 tumours seem to develop in a less immunogenic microenvironment where tumour-promoting inflammation parallels tumourigenesis. Larger studies on non-neoplastic mucosa tissue of mutation carriers are required to better understand the early phases of emerging tumours. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4948DOI Listing
October 2017

DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control.

Nat Genet 2015 Nov 5;47(11):1316-1325. Epub 2015 Oct 5.

BLUEPRINT project.

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.
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http://dx.doi.org/10.1038/ng.3413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444523PMC
November 2015

The PCBP1 gene encoding poly(rC) binding protein I is recurrently mutated in Burkitt lymphoma.

Genes Chromosomes Cancer 2015 Sep 14;54(9):555-64. Epub 2015 Jul 14.

Institute of Human Genetics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

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.
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http://dx.doi.org/10.1002/gcc.22268DOI Listing
September 2015

The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.

Int J Cancer 2015 Dec 6;137(12):2846-57. Epub 2015 Jul 6.

LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.

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.
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http://dx.doi.org/10.1002/ijc.29649DOI Listing
December 2015

Characterization of genomic imbalances in diffuse large B-cell lymphoma by detailed SNP-chip analysis.

Int J Cancer 2015 Mar 22;136(5):1033-42. Epub 2014 Jul 22.

Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.

The pathogenesis of diffuse large B-cell lymphomas (DLBCL) is only partly understood. We analyzed 148 DLBCL by single nucleotide polymorphism (SNP)-chips to characterize genomic imbalances. Seventy-nine cases were of the germinal center B-cell like (GCB) type of DLBCL, 49 of the activated B-cell like (ABC) subtype and 20 were unclassified DLBCL. Twenty-four regions of recurrent genomic gains and 38 regions of recurrent genomic losses were identified over the whole cohort, with a median of 25 imbalances per case for ABC-DLBCL and 19 per case for GCB-DLBCL. Several recurrent copy number changes showed differential frequencies in the GCB- and ABC-DLBCL subgroups, including gains of HDAC7A predominantly in GCB-DLBCL (38% of cases) and losses of BACH2 and CASP8AP2 predominantly in ABC-DLBCL (35%), hinting at disparate pathogenetic mechanisms in these entities. Correlating gene expression and copy number revealed a strong gene dosage effect in all tumors, with 34% of probesets showing a concordant expression change in affected regions. Two new potential tumor suppressor genes emerging from the analysis, CASP3 and IL5RA, were sequenced in ten and 16 candidate cases, respectively. However, no mutations were found, pointing to a potential haploinsufficiency effect of these genes, considering their reduced expression in cases with deletions. Our study thus describes differences and similarities in the landscape of genomic aberrations in the DLBCL subgroups in a large collection of cases, confirming already known targets, but also discovering novel copy number changes with possible pathogenetic relevance.
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http://dx.doi.org/10.1002/ijc.29072DOI Listing
March 2015

A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma.

Blood 2014 Feb 7;123(8):1187-98. Epub 2014 Jan 7.

Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany;

The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by high-level amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation of genes in 11q.
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http://dx.doi.org/10.1182/blood-2013-06-507996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931189PMC
February 2014

Massive transcriptional perturbation in subgroups of diffuse large B-cell lymphomas.

PLoS One 2013 4;8(11):e76287. Epub 2013 Nov 4.

Institute of Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany.

Based on the assumption that molecular mechanisms involved in cancerogenesis are characterized by groups of coordinately expressed genes, we developed and validated a novel method for analyzing transcriptional data called Correlated Gene Set Analysis (CGSA). Using 50 extracted gene sets we identified three different profiles of tumors in a cohort of 364 Diffuse large B-cell (DLBCL) and related mature aggressive B-cell lymphomas other than Burkitt lymphoma. The first profile had high level of expression of genes related to proliferation whereas the second profile exhibited a stromal and immune response phenotype. These two profiles were characterized by a large scale gene activation affecting genes which were recently shown to be epigenetically regulated, and which were enriched in oxidative phosphorylation, energy metabolism and nucleoside biosynthesis. The third and novel profile showed only low global gene activation similar to that found in normal B cells but not cell lines. Our study indicates novel levels of complexity of DLBCL with low or high large scale gene activation related to metabolism and biosynthesis and, within the group of highly activated DLBCLs, differential behavior leading to either a proliferative or a stromal and immune response phenotype.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076287PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817189PMC
August 2014

Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma.

Haematologica 2014 Apr 31;99(4):726-35. Epub 2013 Oct 31.

Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC(+)) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC(+) lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC(+)-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6(+)/MYC(+) and BCL2(+)/MYC(+) double-hit lymphomas. BCL2(+)/MYC(+) double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC(+) lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC(+) lymphomas sharing various molecular characteristics.
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http://dx.doi.org/10.3324/haematol.2013.091827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971083PMC
April 2014

Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing.

Nat Genet 2012 Dec 11;44(12):1316-20. Epub 2012 Nov 11.

Institute of Human Genetics, Christian-Albrechts-University, Kiel, Germany.

Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells. Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci. Consequently, MYC is deregulated, resulting in massive perturbation of gene expression. Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome sequencing of four prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, we identified seven recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma. In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. These findings suggest that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis.
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http://dx.doi.org/10.1038/ng.2469DOI Listing
December 2012

Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis.

Cancer Cell 2012 Aug;22(2):167-79

Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA.

In Burkitt lymphoma (BL), a germinal center B-cell-derived tumor, the pro-apoptotic properties of c-MYC must be counterbalanced. Predicting that survival signals would be delivered by phosphoinositide-3-kinase (PI3K), a major survival determinant in mature B cells, we indeed found that combining constitutive c-MYC expression and PI3K activity in germinal center B cells of the mouse led to BL-like tumors, which fully phenocopy human BL with regard to histology, surface and other markers, and gene expression profile. The tumors also accumulate tertiary mutational events, some of which are recurrent in the human disease. These results and our finding of recurrent PI3K pathway activation in human BL indicate that deregulated c-MYC and PI3K activity cooperate in BL pathogenesis.
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http://dx.doi.org/10.1016/j.ccr.2012.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432451PMC
August 2012

Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults.

Blood 2011 Jul 12;118(1):139-47. Epub 2011 Apr 12.

Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.

The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.
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http://dx.doi.org/10.1182/blood-2011-01-330795DOI Listing
July 2011

Detection of genomic aberrations in molecularly defined Burkitt's lymphoma by array-based, high resolution, single nucleotide polymorphism analysis.

Haematologica 2010 Dec 7;95(12):2047-55. Epub 2010 Sep 7.

Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Virchowstr. 173, 45122 Essen, Germany.

Background: Knowledge about the genetic lesions that occur in Burkitt's lymphoma, besides the pathognomonic IG-MYC translocations, is limited.

Design And Methods: Thirty-nine molecularly-defined Burkitt's lymphomas were analyzed with high-resolution single-nucleotide polymorphism chips for genomic imbalances and uniparental disomy. Imbalances were correlated to expression profiles and selected micro-RNA analysis. Translocations affecting the MYC locus were studied by fluorescence in situ hybridization.

Results: We detected 528 copy number changes, defining 29 recurrently imbalanced regions. Five hundred and eighteen regions of uniparental disomy were found, but these were rarely recurrent. Combined imbalance mapping and expression profiling revealed a strong correlation between copy number and expression. Several recurrent imbalances affected the MYC pathway: the micro-RNA-supercluster 17-92 was frequently gained and the transcription factor E2F2 was recurrently deleted. Molecular Burkitt's lymphoma lacking MYC translocations showed MYC gains. Amplifications of the polymerase iota gene were associated with increased frequency of positions scored as aberrant.

Conclusions: The present findings suggest that uniparental disomies do not play a major role in the pathogenesis of Burkitt's lymphoma, whereas some genes may contribute to the development of this lymphoma through gene dosage effects. Amplifications of the polymerase iota gene may be functionally linked with increased genomic alterations in Burkitt's lymphoma. The pattern and rarity of chromosomal changes detectable, even at the high resolution employed here, together with aberrations of genes regulating MYC activity, support the hypothesis that deregulation of the MYC pathway is the major force driving the pathogenesis of Burkitt's lymphoma, but show that this deregulation is more complex than previously known.
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http://dx.doi.org/10.3324/haematol.2010.026831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995562PMC
December 2010

Cyr61 downmodulation potentiates the anticancer effects of zoledronic acid in androgen-independent prostate cancer cells.

Int J Cancer 2009 Nov;125(9):2004-13

Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy.

We have analyzed the gene modulation induced by zoledronic acid (ZOL) in androgen-resistant prostate cancer PC3 cells with cDNA microarray platform to identify new molecular targets of ZOL in prostate cancer. The gene coding for cysteine-rich, angiogenic inducer, 61 (CYR61) resulted highly downregulated with a fold change of 5.58. Therefore, we have studied the effects of ZOL on CYR61 protein product, and we have found that CYR61 protein expression was decreased significantly after exposure to ZOL. The effect of ZOL on CYR61 expression was dose and time dependent was due to a reduced transcriptional activity of CYR61 promoter. Moreover, the effects induced by ZOL were paralleled by decreased activation of Ras-Raf-1- and Akt-dependent pathways that was dependent from isoprenylation inhibition, since it was antagonized by the addition of geranylgeraniol. Finally, we have investigated the role of CYR61 in the regulation of growth inhibition and invasion/motility of PC3 cells using a shRNA for CYR61 to downregulate the expression of CYR61 protein. The enhanced inhibition of proliferation and motility/invasion induced by ZOL by S-phase accumulation. In the same experimental conditions, CYR61 protein downregulation potentiated the inactivation of the Ras-dependent proliferation pathway and cell cycle inhibitors p21 and p27 expression.
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http://dx.doi.org/10.1002/ijc.24648DOI Listing
November 2009

High-dimensional data analysis: selection of variables, data compression and graphics--application to gene expression.

Biom J 2009 Apr;51(2):235-51

Interdisciplinary Centre for Bioinformatics (IZBI), University of Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany.

The paper presents effective and mathematically exact procedures for selection of variables which are applicable in cases with a very high dimension as, for example, in gene expression analysis. Choosing sets of variables is an important method to increase the power of the statistical conclusions and to facilitate the biological interpretation. For the construction of sets, each single variable is considered as the centre of potential sets of variables. Testing for significance is carried out by means of the Westfall-Young principle based on resampling or by the parametric method of spherical tests. The particular requirements for statistical stability are taken into account; each kind of overfitting is avoided. Thus, high power is attained and the familywise type I error can be kept in spite of the large dimension. To obtain graphical representations by heat maps and curves, a specific data compression technique is applied. Gene expression data from B-cell lymphoma patients serve for the demonstration of the procedures.
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http://dx.doi.org/10.1002/bimj.200800207DOI Listing
April 2009

New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling.

Blood 2009 Mar 15;113(11):2488-97. Epub 2008 Dec 15.

Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.

Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype-specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell-like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling.
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http://dx.doi.org/10.1182/blood-2008-04-152900DOI Listing
March 2009

Microarray-based genomic profiling reveals novel genomic aberrations in follicular lymphoma which associate with patient survival and gene expression status.

Genes Chromosomes Cancer 2009 Jan;48(1):39-54

Abt Innere Medizin III, Zentrum für Innere Medizin der Universität Ulm, Ulm, Germany.

Follicular lymphoma (FL) is characterized by a large number of chromosomal aberrations. However, their exact genomic extension and involved target genes remain to be determined. For this purpose, we used array-based intermediate-high resolution genomic profiling in combination with Affymetrix gene expression analysis. Tumor specimens from 128 FL patients were analyzed for the presence of genomic aberrations and the results were correlated to clinical data sets and mRNA expression levels. In 114 (89%) of the 128 analyzed cases, a total of 688 genomic aberrations (384 gains/amplifications and 304 losses) were detected. Frequent genomic aberrations were: -1p36 (18%), +2p15 (24%), -3q (14%), -6q (25%), +7p (19%), +7q (23%), +8q (14%), -9p (16%), -11q (15%), +12q (20%), -13q (11%), -17p (16%), +18p (18%), and +18q (28%). Critical segments of these imbalances were delineated to genomic fragments with a minimum size down to 0.2 Mb. By comparison of these with mRNA gene expression data, putative candidate genes were identified. Moreover, we found that deletions affecting the tumor suppressor gene CDKN2A/B on 9p21 were detected in nontransformed FL grade I-II. For this aberration as well as for -6q25 and -6q26, an association with inferior survival was observed.
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http://dx.doi.org/10.1002/gcc.20617DOI Listing
January 2009

Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials.

Blood 2008 Aug 28;112(4):1374-81. Epub 2008 May 28.

Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel, Christian-Albrechts-University, Kiel, Germany.

The spectrum of entities, the therapeutic strategy, and the outcome of mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) differs between children and adolescents on the one hand and adult patients on the other. Whereas adult maB-NHLs have been studied in detail, data on molecular profiling of pediatric maB-NHLs are hitherto lacking. We analyzed 65 cases of maB-NHL from patients up to 18 years of age by gene expression profiling, matrix comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH), and immunohistochemistry. The majority of the analyzed pediatric patients were treated within prospective trials (n = 49). We compared this group to a series of 182 previously published cases of adult maB-NHL. Gene expression profiling reclassified 31% of morphologically defined diffuse large B-cell lymphomas as molecular Burkitt lymphoma (mBL). The subgroups obtained by molecular reclassification did not show any difference in outcome in children treated with the NHL-Berlin-Frankfurt-Muenster (BFM) protocols. No differences were detectable between pediatric and adult mBL with regard to gene expression or chromosomal imbalances. This is the first report on molecular profiling of pediatric B-NHL showing mBL to be much more prominent in children than suggested by morphologic assessment. Based on molecular profiling mBL is a molecularly homogeneous disease across children and adults.
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http://dx.doi.org/10.1182/blood-2008-01-136465DOI Listing
August 2008

A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling.

N Engl J Med 2006 Jun;354(23):2419-30

Institute of Pathology, Campus Benjamin Franklin, Charité Universitätsmedizin, Berlin, Germany.

Background: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is unclear. We used transcriptional and genomic profiling to define Burkitt's lymphoma more precisely and to distinguish subgroups in other types of mature aggressive B-cell lymphomas.

Methods: We performed gene-expression profiling using Affymetrix U133A GeneChips with RNA from 220 mature aggressive B-cell lymphomas, including a core group of 8 Burkitt's lymphomas that met all World Health Organization (WHO) criteria. A molecular signature for Burkitt's lymphoma was generated, and chromosomal abnormalities were detected with interphase fluorescence in situ hybridization and array-based comparative genomic hybridization.

Results: We used the molecular signature for Burkitt's lymphoma to identify 44 cases: 11 had the morphologic features of diffuse large-B-cell lymphomas, 4 were unclassifiable mature aggressive B-cell lymphomas, and 29 had a classic or atypical Burkitt's morphologic appearance. Also, five did not have a detectable IG-myc Burkitt's translocation, whereas the others contained an IG-myc fusion, mostly in simple karyotypes. Of the 176 lymphomas without the molecular signature for Burkitt's lymphoma, 155 were diffuse large-B-cell lymphomas. Of these 155 cases, 21 percent had a chromosomal breakpoint at the myc locus associated with complex chromosomal changes and an unfavorable clinical course.

Conclusions: Our molecular definition of Burkitt's lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt's lymphoma. In mature aggressive B-cell lymphomas without a gene signature for Burkitt's lymphoma, chromosomal breakpoints at the myc locus were associated with an adverse clinical outcome.
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http://dx.doi.org/10.1056/NEJMoa055351DOI Listing
June 2006
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