Improving Seroreactivity-Based Detection of Glioma

Ludwig, Nicole; Keller, Andreas; Heisel, Sabrina; Leidinger, Petra; Klein, Veronika; Rheinheimer, Stefanie; Andrès, C.; Stephan, B.; Steudel, Wolf-Ingo; Graf, Norbert; Burgeth, Bernhard; Weickert, Joachim; Lenhof, Hans‐Peter; Meese, Eckart

doi:10.1593/neo.91018

Cited by 23 publications

(36 citation statements)

References 37 publications

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“…The hypothesis that SNPs are associated with immunogenic antigens was first proposed by Stadler et al [25]. This idea is also supported by our finding of SNPs in genes previously associated with humoral immune response in glioma patients [26], [35].…”

Section: Discussionsupporting

confidence: 85%

Identification of Novel SNPs in Glioblastoma Using Targeted Resequencing

et al. 2011

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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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Section: Discussionsupporting

confidence: 85%

Identification of Novel SNPs in Glioblastoma Using Targeted Resequencing

et al. 2011

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“…Protein macroarray screening was carried out as previously described [21], [27], [28]. In brief, a high-density protein macroarray containing 38,016 E.coli expressed peptide clones from the hex1 library [31] had been pre-screened with 150 sera from patients with various conditions, including cancer and autoimmune diseases.…”

Section: Methodsmentioning

confidence: 99%

“…Standardized evaluation of the scanned images was carried out by a previously described computer aided image analysis procedure [27], [28]. In pre-processing steps images were adjusted and edges virtually cut.…”

Section: Methodsmentioning

confidence: 99%

“…The frequency of positive seroreactivities among the groups of patients with MG and healthy controls against a given peptide clone was calculated after arbitrarily defining intensity values ≥50 as positive and intensity values <50 as negative [28]. Statistical significance of different frequencies of serum autoantibodies was determined using two-tailed Fisher's exact probability test.…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, previous work performed in patients with various cancers as well as autoimmune diseases suggests that autoantibody profiles may have the potential to serve as disease biomarkers and to provide clues for disease pathogenesis [20], [21], [22], [23], [24], [25], [26]. Accordingly, a customized protein macroarray comprising 1827 potential human autoantigens recently developed in our laboratory permitted to adequately discriminate sera of patients with different cancers from sera of healthy controls [27], [28], [29]. However, this customized macroarray has not yet been evaluated in antibody-mediated autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

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Myasthenia Gravis: Analysis of Serum Autoantibody Reactivities to 1827 Potential Human Autoantigens by Protein Macroarrays

et al. 2013

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BackgroundMyasthenia gravis is a disorder of neuromuscular transmission associated with autoantibodies against the nicotinic acetylcholine receptor. We have previously developed a customized protein macroarray comprising 1827 potential human autoantigens, which permitted to discriminate sera of patients with different cancers from sera of healthy controls, but has not yet been evaluated in antibody-mediated autoimmune diseases.ObjectiveTo determine whether autoantibody signatures obtained by protein macroarray separate sera of patients with myasthenia gravis from healthy controls.MethodsSera of patients with acetylcholine receptor antibody-positive myasthenia gravis (n = 25) and healthy controls (n = 32) were analyzed by protein macroarrays comprising 1827 peptide clones.ResultsAutoantibody signatures did not separate patients with myasthenia gravis from controls with sufficient sensitivity, specificity, and accuracy. Intensity values of one antigen (poly A binding protein cytoplasmic 1, p = 0.0045) were higher in patients with myasthenia gravis, but the relevance of this and two further antigens, 40S ribosomal protein S13 (20.8% vs. 0%, p = 0.011) and proteasome subunit alpha type 1 (25% vs. 3.1%, p = 0.035), which were detected more frequently by myasthenia gravis than by control sera, currently remains uncertain.ConclusionSeroreactivity profiles of patients with myasthenia gravis detected by a customized protein macroarray did not allow discrimination from healthy controls, compatible with the notion that the autoantibody response in myasthenia gravis is highly focussed against the acetylcholine receptor.

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Novel immunogenic antigens increase classification accuracy in meningioma to 93.84%

Ludwig

Keller

Heisel

et al. 2011

Intl Journal of Cancer

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There is growing evidence that simultaneous analysis of multiple autoantibody reactions can be utilized for diagnosis of neoplasms. Using a set of 57 meningioma-associated antigens, we recently separated meningioma patients from individuals without known disease with an accuracy of 90.3%. Here, we ask whether a largely increased set of immunogenic antigens can further improve this discrimination. We used an array with 1,827 human recombinant clones and measured reactivity of serum autoantibodies against the clones by a novel automated image analysis procedure. We were able to separate meningioma sera from sera of healthy controls with a specificity of 95.62%, a sensitivity of 91.83% and an accuracy of 93.84%. Of the analyzed clones, 23 in-frame clones were highly informative for the classification of meningioma vs. normal sera as shown by their AUC values. These results demonstrate that the accuracy of a serum-based diagnostic can be readily and considerably improved by screening extended sets of proteins.

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Improving Seroreactivity-Based Detection of Glioma

Cited by 23 publications

References 37 publications

Identification of Novel SNPs in Glioblastoma Using Targeted Resequencing

Identification of Novel SNPs in Glioblastoma Using Targeted Resequencing

Myasthenia Gravis: Analysis of Serum Autoantibody Reactivities to 1827 Potential Human Autoantigens by Protein Macroarrays

Novel immunogenic antigens increase classification accuracy in meningioma to 93.84%

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