Array comparative genomic hybridization of canine diffuse large B-cell lymphoma (cDLBCL)
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ABSTRACT:
ORGANISM(S): Canis lupus familiaris
PROVIDER: GSE113258 | GEO | 2019/05/01
REPOSITORIES: GEO
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Project description:In this study, we present the first comparison of global transcriptional changes taking place in canine lymphoma and human diffuse large B-cell lymphoma (DLBCL), with particular reference to the nuclear factor-kappaB (NF-?B) pathway. Microarray data generated from lymph nodes diagnosed with canine DLBCL and healthy lymph nodes were used for differential expression analysis, co-expression analysis and pathway analysis, and compared with analysis of publicly available microarray data from human healthy and DLBCL lymph nodes. The comparisons between species at gene level were performed by mapping the probesets in canine microarrays to orthologous genes in humans and vice versa. A considerable number of differentially expressed genes between canine lymphoma and healthy lymph node samples were also found differentially expressed between human DLBCL and healthy lymph node samples. Principal component analysis (PCA) using a literature derived 120 NF-?B target gene set mapped to 199 orthologous canine array probesets and 259 human array probesets clearly separated the healthy and cancer samples in both canine and human datasets. The analysis demonstrated that for both human and canine DLBCL there is activation of the NF-?B/p65 canonical pathway rather than the alternative pathway. This has therapeutic implications for the use of specific pathway inhibitors for the treatment of DLBCL for both species and also indicates that naturally occurring canine lymphoma could be used as a model to study therapeutic strategies for human lymphoma. The model was further validated by the identification of molecular signatures that could sub-classify canine DLBCL into activated B-cell-like (ABC) or germinal centre B-cell-like (GCB) types equivalent to human subtypes. Canine DLBCL patients were recruited via the clinical oncology service of the University of Edinburgh Royal (Dick) School of Veterinary Studies (DJA), and the University of Wisconsin-Madison School of Veterinary Medicine (DMV). Lymph node biopsy samples were taken, as part of normal diagnostic procedures, from dogs newly diagnosed with lymphoma (naïve) and samples from dogs that had relapsed following standard of care CHOP chemotherapy. Only dogs with confirmed DLBCL after pathological grading were used in this study. This included standard histopathological grading by two independent pathologists and CD3/PAX5 marker analysis. Normal lymph node samples were obtained from canines that were euthanized for non-lymphoma conditions. Microarray data were generated from 35 canine samples (25 DLBCL and 10 healthy) in total. However, data from 2 canine DLBCL samples did not meet our required quality and were removed from further analysis. Only data from 33 (23 DLBCL and 10 healthy) samples were used for analysis. The generated data were used for differential expression analysis, co-expression analysis and pathway analysis, and compared with analysis of publicly available microarray data (GSE12195) from human healthy and DLBCL lymph nodes. The comparisons between species at gene level were performed by mapping the probesets in canine microarrays to orthologous genes in humans and vice versa.
2013-09-26 | E-GEOD-30881 | biostudies-arrayexpress
Project description:MCL1 is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared to germinal center B-cell-like (GCB) DLBCL patient samples (p=2.7 x 10(-10)) [PMID 23257783]. Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; p=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization (aCGH) data of 203 DLBCL samples [GSE11318] and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1 positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs. This GEO dataset is comprised of aCGH measurements for DLBCL cell lines, which are used in the above-mentioned paper. Cell lines were measured against the DNA of a healthy male donor who in turn was measured against a pool of healthy DNAs to correct for individual CNVs of the donor.
2013-01-04 | E-GEOD-43272 | biostudies-arrayexpress
Project description:Introduction: Lymphoma is a common canine cancer with translational relevance to human disease. Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype, contributing to almost fifty percent of clinically recognized lymphoma cases. Identifying new biomarkers capable of early diagnosis and monitoring DLBCL is crucial for enhancing remission rates. This research seeks to advance our knowledge of the molecular biology of DLBCL by analyzing the expression of microRNAs, which regulate gene expression by negatively impacting gene expression via targeted RNA degradation or translational re-pression. The stability and accessibility of microRNAs make them appropriate biomarkers for the diagnosis, prognosis, and monitoring of diseases. Methods: We extracted and sequenced microRNAs from ten fresh-frozen lymph node tissue samples (six DLBCL and four non-neoplastic). Results: Small RNA sequencing data analysis revealed 35 differently expressed miRNAs (DEMs) compared to controls. RT-qPCR confirmed that 23/35 DEMs in DLBCL were significantly upregulated (n = 14) or downregulated (n = 9). Statistical significance was determined by comparing each miRNA's average expression fold-change (2-Cq) between the DLCBL and healthy groups by applying the unpaired parametric Welch's 2-sample t-test and false discovery rate (FDR). The predicted target genes of the DEMs were mainly enriched in the PI3K-Akt-MAPK pathway. Discussion: Our data point to the potential value of miRNA signatures as diagnostic biomarkers and serve as a guideline for subsequent experimental studies to determine the targets and functions of these altered miRNAs in canine DLBCL.
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Project description:This study centered on using a custom made Nimblegen aCGH chip that targeted all segmental duplications in the canine genome to identify associated CNVs. A total of 19 hybridizations were performed in a panel of diverse dogs and a single wolf.
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Project description:This study centered on using a custom made Nimblegen aCGH chip that targeted all segmental duplications in the canine genome to identify associated CNVs. A total of 19 hybridizations were performed in a panel of diverse dogs and a single wolf. Using computational approaches all segmental duplications were identified in the canFam2 genome of the dog. A custom aCGH chip was then built that densely interrogated these segmental duplications for CNVs in a panel of diverse dog breeds and a single wolf.
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Project description:Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumors. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumors of DLBCL patients, apparently reflecting the variation in tumor proliferation rate, host response and differentiation state of the tumor. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal center B cells ('germinal center B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal center B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumors on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer. This study is described more fully in Alizadeh AA et al.(2000) Nature 403:503-11
2002-06-27 | E-GEOD-60 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumors. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumors of DLBCL patients, apparently reflecting the variation in tumor proliferation rate, host response and differentiation state of the tumor. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal center B cells ('germinal center B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal center B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumors on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer. This study is described more fully in Alizadeh AA et al.(2000) Nature 403:503-11 Keywords: other
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