P13.11 Metabolomics and molecular profiling in glioma patients: an interactomic approach

Abstract BACKGROUND A wider view of the interaction between different omic-domains is needed to identify potential biomarkers of low- and high-grade gliomas. Using an interactomic approach, we analyzed the correlation between radiological data, IDH mutation, gene expression profiling and metabolic signature in glioma samples. MATERIAL AND METHODS Tumor biopsies from 25 patients with clinical diagnosis of glioma were surgically collected during 2017–2019 at the senior author’s institution. Metabolomic data was obtained by high resolution 31P and 1H magnetic resonance spectroscopy (MRS, 19 metabolites quantified with LCModel). Gene expression profiling was performed using real-time qPCR of 19 genes related to energy metabolism. IDH1/2 common mutation (IDH1R132H/IDH2R172H) was verified by immunohistochemistry and amplicon sanger sequencing. All data was integrated using the R package mixOmics, and we built correlation network plot graphs and correlation maps to identify the most significant interactions, that were analyzed thereafter. RESULTS Mean age was 48±10 years and 72% were men. The most frequent clinical presentation was intracranial hypertension and focal deficit. Imaging revealed 88% of single lobar tumors, 96% of contrast enhancement, 52% located near eloquent areas, 48% with augmented perfusion (mean values of 300±130%) and 60% showed restricted diffusion. WHO 2016 diagnosis were glioblastoma IDH mutated (IDHmut, 16%), IDH wildtype (IDHw, 56%); anaplastic astrocytoma IDHmut (4%), IDHw (16%); diffuse astrocytoma IDHmut (4%), SEGA (4%). The genetic and metabolic profiles were normalized per sample using the total sum of all the studied variables per case. This step made the interactomic approach possible. We found no differences between the metabolic or genetic profiles of glioma grade III and IV samples. However, there was a statistical significance or near-threshold correlation between some metabolic patterns and IDH-mutation, where Alanine (4.7±1.3% IDHw vs 2.5±0.7 IDHmut, p=0.046), Glycine (2.7±0.5% vs. 1.6±0.4%, p=0.095), Glycerophosphorylcholine (3.9±0.4% vs. 6.4±0.9%, p=0.013) and Myo-inositol (4.9±1.0% vs 11.9±2.1%, p=0.004) were the most important biomarkers. Overexpression of Lactate Dehydrogenase subunit B (LDHB, 19±3% vs. 31±6%, p=0.039) and Aconitase 1 (ACO1, 0.5±0.1% vs 1.2±0.3%, p=0.08) had also a significant or near-threshold relationship with IDH-mutation. These correlations were shown as hot spots in the correlation graphs and maps. CONCLUSION These preliminary results indicate that metabolic patterns by high resolution 31P and 1H MRS could be a useful tool to improve our knowledge about glioma gene expression profiles and to identify potential biomarkers to tackle this pathology.

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A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number

Laboratory Investigation ◽

10.1038/labinvest.2010.110 ◽

2010 ◽

Vol 90 (9) ◽

pp. 1285-1294 ◽

Cited By ~ 60

Author(s):

Annalisa Astolfi ◽

Margherita Nannini ◽

Maria Abbondanza Pantaleo ◽

Monica Di Battista ◽

Michael C Heinrich ◽

...

Keyword(s):

Gene Expression ◽

High Resolution ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Copy Number ◽

Gastrointestinal Stromal Tumors ◽

Integrative Analysis ◽

Stromal Tumors ◽

Genomic Copy Number ◽

Genomic Copy

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High Resolution Gene Expression Profiling of RNA Synthesis, Processing, and Decay by Metabolic Labeling of Newly Transcribed RNA Using 4-Thiouridine

Methods in Molecular Biology - Virus-Host Interactions ◽

10.1007/978-1-62703-601-6_6 ◽

2013 ◽

pp. 91-100 ◽

Cited By ~ 13

Author(s):

Lars Dölken

Keyword(s):

Gene Expression ◽

High Resolution ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Rna Synthesis ◽

Metabolic Labeling

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High-Resolution Gene Expression Profiling of RNA Synthesis, Processing, and Decay by Metabolic Labeling of Newly Transcribed RNA Using 4-Thiouridine

Methods in Molecular Biology - Eukaryotic Transcriptional and Post-Transcriptional Gene Expression Regulation ◽

10.1007/978-1-4939-6518-2_10 ◽

2016 ◽

pp. 129-140 ◽

Cited By ~ 5

Author(s):

Andrzej J. Rutkowski ◽

Lars Dölken

Keyword(s):

Gene Expression ◽

High Resolution ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Rna Synthesis ◽

Metabolic Labeling

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Clonotypic Bone Marrow-Derived Endothelial Progenitor Cells in Multiple Myeloma.

Blood ◽

10.1182/blood.v108.11.3497.3497 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3497-3497

Author(s):

Marc J. Braunstein ◽

Daniel R. Carrasco ◽

David Kahn ◽

Kumar Sukhdeo ◽

Alexei Protopopov ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Bone Marrow ◽

High Resolution ◽

Gene Expression Profiling ◽

Progenitor Cells ◽

Tumor Cells ◽

Endothelial Progenitor Cells ◽

Expression Profiling ◽

Gains And Losses

Abstract In multiple myeloma (MM), bone marrow-derived endothelial progenitor cells (EPCs) contribute to tumor neoangiogenesis and their levels covary with tumor mass and prognosis. Recent X-chromosome inactivation studies in female patients showed that, similar to tumor cells, EPCs are clonally restricted in MM. Genomic profiling of MM using high-resolution array comparative genomic hybridization (aCGH) has been previously utilized to mine the genome and find clinical correlates in MM patients. In this study, clonotypic aspects of bone marrow-derived EPCs and MM cells were investigated using aCGH and expression profiling analysis. Confluent EPCs were outgrown from bone marrow aspirates by adherence to laminin. EPCs were >98% vWF/CD133/KDR+ and <1% CD38+. The laminin-nonadherent bone marrow fraction enriched for tumor cells was >50% CD38+. For aCGH and for gene expression profiling, genomic DNA and total RNA from EPCs and MM cells were hybridized to human oligonucleotide arrays (Agilent Technologies) and human cDNA microarrays (Affymetrix), respectively. High resolution aCGH with segmentation analysis showed that EPCs and MM cells in one of ten cases share identical patterns of chromosomal gains and losses, while another 5 cases shared multiple focal copy number alterations (CNAs) including gains and losses. The genomes of EPCs and MM cells additionally displayed exclusive CNAs, but these were far fewer in EPCs than in MM cells. In 3 patients, EPCs harbored a common 0.6Mb deletion at 1q21 not shared by MM cells. Pertinent genes in this region that could affect proliferation and tumor suppression include N2N, NBPF10, and TXNIP. Validation studies of aCGH findings by other methods are ongoing. Gene expression profiling showed decreased expression of 1q21 region genes (e.g., calgranulin C and lamin A/C). A genome-wide comparison of patients’ MM cells and EPCs, which is focused on their shared genetic characteristics, will be presented.

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Metabolic Labeling of Newly Transcribed RNA for High Resolution Gene Expression Profiling of RNA Synthesis, Processing and Decay in Cell Culture

Journal of Visualized Experiments ◽

10.3791/50195 ◽

2013 ◽

Cited By ~ 23

Author(s):

Bernd Rädle ◽

Andrzej J. Rutkowski ◽

Zsolt Ruzsics ◽

Caroline C. Friedel ◽

Ulrich H. Koszinowski ◽

...

Keyword(s):

Gene Expression ◽

Cell Culture ◽

High Resolution ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Rna Synthesis ◽

Metabolic Labeling

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Gene Expression Profiling in a Mouse Model Identifies Fetal Liver- and Placenta-Derived Potential Biomarkers for Down Syndrome Screening

PLoS ONE ◽

10.1371/journal.pone.0018866 ◽

2011 ◽

Vol 6 (4) ◽

pp. e18866 ◽

Cited By ~ 16

Author(s):

Jeroen L. A. Pennings ◽

Wendy Rodenburg ◽

Sandra Imholz ◽

Maria P. H. Koster ◽

Conny T. M. van Oostrom ◽

...

Keyword(s):

Gene Expression ◽

Down Syndrome ◽

Mouse Model ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Fetal Liver ◽

Potential Biomarkers ◽

Down Syndrome Screening

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Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-mediate gastrointestinal adverse events.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8593 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8593-8593 ◽

Cited By ~ 1

Author(s):

Vafa Shahabi ◽

David Mark Berman ◽

Scott D. Chasalow ◽

Lisu Wang ◽

Zenta Tsuchihashi ◽

...

Keyword(s):

Gene Expression ◽

Adverse Events ◽

Gene Expression Profiling ◽

Whole Blood ◽

Expression Profiling ◽

Repeated Measures ◽

Predictive Biomarkers ◽

Activation Markers ◽

Over Time ◽

Potential Biomarkers

8593 Background: Treatment with ipilimumab, a fully human anti-CTLA-4 antibody approved for treatment of metastatic melanoma (MM), is associated with a number of immune-mediated Adverse Events (imAEs) such as colitis and skin rash. Predictive biomarkers that can help identify patients (pts) who might experience these imAEs could enhance the management of these toxicities. Methods: Gene expression profiling (using Affymetrix gene chip HT-HG-U133A) was performed on the whole blood samples from 162 MM pts at baseline, 3 and 11 weeks after the start of ipilimumab treatment in two phase II clinical trials (CA184004 and -007). Overall, 49 pts experienced Grade 2 or higher GI-imAE (G2+) during the course of treatment. A repeated measures ANOVA was used to evaluate the differences in mean expression levels between the two groups and at the three time points. Uncorrected p-value of 0.05 was used as a cutoff for this analysis. Results: In baseline samples, 27 probe sets showed differential mean expression (≥ 1.5 fold, p < 0.05) between G2+ pts and others. Most of these genes belonged to three functional categories: immune system, cell cycle or intracellular trafficking. Changes in gene expression over time were also characterized. In the G2+ pts, 58 and 247 genes had a ≥ 1.5 fold (p < 0.05) change in expression from baseline to week 3 and 11 post-treatment, respectively, compared to 17 and 73 in other pts. In particular, the on-treatment increases of the expression of CD177 and CEACAM1, two neutrophil activation markers, were closely associated with G2+ GI-imAE, suggesting a possible role of neutrophils in ipilimumab associated GI-imAEs. In addition, the expression of several Ig genes increased over time, with higher increases in the G2+ pts. These observations were reproduced in another ipilimumab monotherapy study in MM (CA184078). Conclusions: Gene expression profiling of peripheral blood resulted in the identification of a set of potential biomarkers that may be predictive of severe GI-imAEs before, or early in the course of treatment with ipilimumab. Further validation of these biomarkers in a larger patient cohort is warranted.

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