Biomarker Discovery Center Heidelberg

Heidelberg, Germany

Biomarker Discovery Center Heidelberg

Heidelberg, Germany
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Hausler S.F.M.,University of Würzburg | Keller A.,Febit Biomedical Gmbh | Keller A.,Biomarker Discovery Center Heidelberg | Chandran P.A.,University of Würzburg | And 9 more authors.
British Journal of Cancer | Year: 2010

Background: Screening is an unsolved problem for ovarian cancer (OvCA). As late detection is equivalent to poor prognosis, we analysed whether OvCA patients show diagnostically meaningful microRNA (miRNA) patterns in blood cells. Methods: Blood-borne whole miRNome profiles from 24 patients with OvCA and 15 age-and sex-matched healthy controls were biostatistically evaluated. Results: Student's t-test revealed 147 significantly deregulated miRNAs before and 4 after Benjamini-Hochberg adjustment. Although these included miRNAs already linked to OvCA (e.g., miR-16, miR-155), others had never before been connected to specific diseases. A bioinformatically calculated miRNA profile allowed for discrimination between blood samples of OvCA patients and healthy controls with an accuracy of >76%. When only cancers of the serous subtype were considered and compared with an extended control group (n=39), accuracy, specificity and sensitivity all increased to >85%. Conclusion: Our proof-of-principle study strengthens the hypothesis that neoplastic diseases generate characteristic miRNA fingerprints in blood cells. Still, the obtained OvCA-associated miRNA pattern is not yet sensitive and specific enough to permit the monitoring of disease progression or even preventive screening. Microarray-based miRNA profiling from peripheral blood could thus be combined with other markers to improve the notoriously difficult but important screening for OvCA. © 2010 Cancer Research UK All rights reserved.


Leidinger P.,Saarland University | Keller A.,Febit Biomedical gmbh | Keller A.,Biomarker Discovery Center Heidelberg | Borries A.,Febit Biomedical gmbh | And 5 more authors.
BMC Cancer | Year: 2010

Background: MicroRNA (miRNA) signatures are not only found in cancer tissue but also in blood of cancer patients. Specifically, miRNA detection in blood offers the prospect of a non-invasive analysis tool.Methods: Using a microarray based approach we screened almost 900 human miRNAs to detect miRNAs that are deregulated in their expression in blood cells of melanoma patients. We analyzed 55 blood samples, including 20 samples of healthy individuals, 24 samples of melanoma patients as test set, and 11 samples of melanoma patients as independent validation set.Results: A hypothesis test based approch detected 51 differentially regulated miRNAs, including 21 miRNAs that were downregulated in blood cells of melanoma patients and 30 miRNAs that were upregulated in blood cells of melanoma patients as compared to blood cells of healthy controls. The tets set and the independent validation set of the melanoma samples showed a high correlation of fold changes (0.81). Applying hierarchical clustering and principal component analysis we found that blood samples of melanoma patients and healthy individuals can be well differentiated from each other based on miRNA expression analysis. Using a subset of 16 significant deregulated miRNAs, we were able to reach a classification accuracy of 97.4%, a specificity of 95% and a sensitivity of 98.9% by supervised analysis. MiRNA microarray data were validated by qRT-PCR.Conclusions: Our study provides strong evidence for miRNA expression signatures of blood cells as useful biomarkers for melanoma. © 2010 Leidinger et al; licensee BioMed Central Ltd.


Meder B.,University of Heidelberg | Keller A.,Biomarker Discovery Center Heidelberg | Vogel B.,University of Heidelberg | Haas J.,University of Heidelberg | And 9 more authors.
Basic Research in Cardiology | Year: 2011

MicroRNAs (miRNAs) are important regulators of adaptive and maladaptive responses in cardiovascular diseases and hence are considered to be potential therapeutical targets. However, their role as novel biomarkers for the diagnosis of cardiovascular diseases still needs to be systematically evaluated. We assessed here for the first time whole-genome miRNA expression in peripheral total blood samples of patients with acute myocardial infarction (AMI). We identified 121 miRNAs, which are significantly dysregulated in AMI patients in comparison to healthy controls. Among these, miR-1291 and miR-663b show the highest sensitivity and specificity for the discrimination of cases from controls. Using a novel self-learning pattern recognition algorithm, we identified a unique signature of 20 miRNAs that predicts AMI with even higher power (specificity 96%, sensitivity 90%, and accuracy 93%). In addition, we show that miR-30c and miR-145 levels correlate with infarct sizes estimated by Troponin T release. The here presented study shows that single miRNAs and especially miRNA signatures derived from peripheral blood, could be valuable novel biomarkers for cardiovascular diseases. © 2010 Springer-Verlag.


Keller A.,Biomarker Discovery Center Heidelberg | Keller A.,Saarland University | Keller A.,Siemens AG | Backes C.,Biomarker Discovery Center Heidelberg | And 13 more authors.
Molecular BioSystems | Year: 2011

MicroRNAs (miRNAs) are increasingly envisaged as biomarkers for various tumor and non-tumor diseases. MiRNA biomarker identification is, as of now, mostly performed in a candidate approach, limiting discovery to annotated miRNAs and ignoring unknown ones with potential diagnostic value. Here, we applied high-throughput SOLiD transcriptome sequencing of miRNAs expressed in human peripheral blood of patients with lung cancer. We developed a bioinformatics pipeline to generate profiles of miRNA markers and to detect novel miRNAs with diagnostic information. Applying our approach, we detected 76 previously unknown miRNAs and 41 novel mature forms of known precursors. In addition, we identified 32 annotated and seven unknown miRNAs that were significantly altered in cancer patients. These results demonstrate that deep sequencing of small RNAs bears high potential to quantify miRNAs in peripheral blood and to identify previously unknown miRNAs serving as biomarker for lung cancer. © 2011 The Royal Society of Chemistry.


Keller A.,Biomarker Discovery Center Heidelberg | Harz C.,Saarland University | Matzas M.,Biomarker Discovery Center Heidelberg | Meder B.,University of Heidelberg | And 4 more authors.
PLoS ONE | Year: 2011

High-throughput sequencing opens avenues to find genetic variations that may be indicative of an increased risk for certain diseases. Linking these genomic data to other "omics" approaches bears the potential to deepen our understanding of pathogenic processes at the molecular level. To detect novel single nucleotide polymorphisms (SNPs) for glioblastoma multiforme (GBM), we used a combination of specific target selection and next generation sequencing (NGS). We generated a microarray covering the exonic regions of 132 GBM associated genes to enrich target sequences in two GBM tissues and corresponding leukocytes of the patients. Enriched target genes were sequenced with Illumina and the resulting reads were mapped to the human genome. With this approach we identified over 6000 SNPs, including over 1300 SNPs located in the targeted genes. Integrating the genome-wide association study (GWAS) catalog and known disease associated SNPs, we found that several of the detected SNPs were previously associated with smoking behavior, body mass index, breast cancer and high-grade glioma. Particularly, the breast cancer associated allele of rs660118 SNP in the gene SART1 showed a near doubled frequency in glioblastoma patients, as verified in an independent control cohort by Sanger sequencing. In addition, we identified SNPs in 20 of 21 GBM associated antigens providing further evidence that genetic variations are significantly associated with the immunogenicity of antigens. © 2011 Keller et al.


Vogel B.,University of Heidelberg | Vogel B.,German Center for Cardiovascular Research | Keller A.,Biomarker Discovery Center Heidelberg | Keller A.,Saarland University | And 16 more authors.
European Heart Journal | Year: 2013

AimsNon-ischaemic heart failure is one of the today's most prevalent cardiovascular disorders. Since modern pharmacotherapy has proved to be very effective in delaying disease progression and preventing death, imaging modalities and molecular biomarkers play an important role in early identification and clinical management as well as risk assessment of patients. The present study evaluated for the first time whole peripheral blood miRNAs as novel biomarker candidates for non-ischaemic heart failure with reduced ejection fraction (HF-REF). Methods and results We assessed genome-wide miRNA expression profiles in 53 HF-REF patients and 39 controls. We could identify and validate several miRNAs that show altered expression levels in non-ischaemic HF-REF, discriminating cases from controls both as single markers or when combined in a multivariate signature. In addition, we demonstrate that the miRNAs of this signature significantly correlate with disease severity as indicated by left ventricular ejection fraction. Conclusion Our data further denote that miRNAs are potential biomarkers for systolic heart failure. Since their detection levels in whole blood are also related to the degree of left ventricular dysfunction, they may serve as objective molecular tools to assess disease severity and prognosis. © 2013 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013.


Roth P.,University of Zürich | Wischhusen J.,University of Würzburg | Happold C.,University of Zürich | Chandran P.A.,University of Würzburg | And 6 more authors.
Journal of Neurochemistry | Year: 2011

The prognosis of patients afflicted by glioblastoma remains poor. Biomarkers for the disease would be desirable in order to allow for an early detection of tumor progression or to indicate rapidly growing tumor subtypes requiring more intensive therapy. In this study, we investigated whether a blood-derived specific miRNA fingerprint can be defined in patients with glioblastoma. To this end, miRNA profiles from the blood of 20 patients with glioblastoma and 20 age- and sex-matched healthy controls were compared. Of 1158 tested miRNAs, 52 were significantly deregulated, as assessed by unadjusted Student′s t-test at an alpha level of 0.05. Of these, two candidates, miR-128 (up-regulated) and miR-342-3p (down-regulated), remained significant after correcting for multiple testing by Benjamini-Hochberg adjustment with a p-value of 0.025. The altered expression of these two biomarkers was confirmed in a second cohort of glioblastoma patients and healthy controls by real-time PCR and validated for patients who had received neither radio- nor chemotherapy and for patients who had their glioblastomas resected more than 6 months ago. Moreover, using machine learning, a comprehensive miRNA signature was obtained that allowed for the discrimination between blood samples of glioblastoma patients and healthy controls with an accuracy of 81% [95% confidence interval (CI) 78-84%], specificity of 79% (95% CI 75-83%) and sensitivity of 83% (95% CI 71-85%). In summary, our proof-of-concept study demonstrates that blood-derived glioblastoma-associated characteristic miRNA fingerprints may be suitable biomarkers and warrant further exploration. © 2011 International Society for Neurochemistry.


PubMed | Biomarker Discovery Center Heidelberg
Type: Journal Article | Journal: RNA biology | Year: 2011

Circulating microRNAs in human serum have increasingly been recognized as stable markers for cancer detection. However, there is still a lack of miRNome wide studies over a long period of time with respect to pathogenic processes. We obtained serum samples from the janus serum bank collected prior and after diagnosis of lung cancer. We analyzed the abundance of 904 miRNAs in serum from eight cancer patients at three time points and from six healthy control individuals. Based on the identified miRNA signatures, hierarchical clustering and a self-organizing map identified three major clusters including one cluster containing most of the of the pre-diagnostic samples, a second cluster with mainly post-diagnostic samples, and a third cluster with mainly control samples. Correlation analyses showed that although the profiles were generally stable over several years, most obvious changes of the miRNA pattern seem to occur at a time close to diagnosis. Our findings support the idea that a developing lung cancer might be detectable years prior to diagnosis through a specific miRNA signature and that this signature changes during tumor development.


PubMed | Biomarker Discovery Center Heidelberg
Type: Journal Article | Journal: Molecular bioSystems | Year: 2011

MicroRNAs (miRNAs) are increasingly envisaged as biomarkers for various tumor and non-tumor diseases. MiRNA biomarker identification is, as of now, mostly performed in a candidate approach, limiting discovery to annotated miRNAs and ignoring unknown ones with potential diagnostic value. Here, we applied high-throughput SOLiD transcriptome sequencing of miRNAs expressed in human peripheral blood of patients with lung cancer. We developed a bioinformatics pipeline to generate profiles of miRNA markers and to detect novel miRNAs with diagnostic information. Applying our approach, we detected 76 previously unknown miRNAs and 41 novel mature forms of known precursors. In addition, we identified 32 annotated and seven unknown miRNAs that were significantly altered in cancer patients. These results demonstrate that deep sequencing of small RNAs bears high potential to quantify miRNAs in peripheral blood and to identify previously unknown miRNAs serving as biomarker for lung cancer.


PubMed | Biomarker Discovery Center Heidelberg
Type: Journal Article | Journal: PloS one | Year: 2011

High-throughput sequencing opens avenues to find genetic variations that may be indicative of an increased risk for certain diseases. Linking these genomic data to other omics approaches bears the potential to deepen our understanding of pathogenic processes at the molecular level. To detect novel single nucleotide polymorphisms (SNPs) for glioblastoma multiforme (GBM), we used a combination of specific target selection and next generation sequencing (NGS). We generated a microarray covering the exonic regions of 132 GBM associated genes to enrich target sequences in two GBM tissues and corresponding leukocytes of the patients. Enriched target genes were sequenced with Illumina and the resulting reads were mapped to the human genome. With this approach we identified over 6000 SNPs, including over 1300 SNPs located in the targeted genes. Integrating the genome-wide association study (GWAS) catalog and known disease associated SNPs, we found that several of the detected SNPs were previously associated with smoking behavior, body mass index, breast cancer and high-grade glioma. Particularly, the breast cancer associated allele of rs660118 SNP in the gene SART1 showed a near doubled frequency in glioblastoma patients, as verified in an independent control cohort by Sanger sequencing. In addition, we identified SNPs in 20 of 21 GBM associated antigens providing further evidence that genetic variations are significantly associated with the immunogenicity of antigens.

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