The genomic landscape of germinal center derived B-cell lymphomas other than follicular, diffuse-large B-cell and Burkitt lymphom
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PROVIDER: EGAS00001002422 | EGA |
REPOSITORIES: EGA
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Project description:As part of the ICGC, the ICGC MMML-Seq project performed whole genome sequencing and RNA sequencing of follicular and diffuse large B-cell lymphoma. Follicular and diffuse large B-cell lymphomas are the most common B-cell lymphomas in adulthood. Analyses were performed in concordance with the guidelines of the ICGC. The results define the genomic landscape of structural variants, somatic single nucleotide variants and mutational signatures in these lymphomas
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Project description:Serine-threonine kinase CK2 is highly expressed and pivotal for survival and proliferation in multiple myeloma, chronic lymphocytic leukemia and mantle cell lymphoma. Here, we investigated the expression of ? catalytic and ? regulatory CK2 subunits by immunohistochemistry in 57 follicular (FL), 18 Burkitt (BL), 52 diffuse large B-cell (DLBCL) non-Hodgkin lymphomas (NHL) and in normal reactive follicles. In silico evaluation of available Gene Expression Profile (GEP) data sets from patients and Western blot (WB) analysis in NHL cell-lines were also performed. Moreover, the novel, clinical-grade, ATP-competitive CK2-inhibitor CX-4945 (Silmitasertib) was assayed on lymphoma cells. CK2 was detected in 98.4% of cases with a trend towards a stronger CK2? immunostain in BL compared to FL and DLBCL. No significant differences were observed between Germinal Center B (GCB) and non-GCB DLBCL types. GEP data and WB confirmed elevated CK2 mRNA and protein levels as well as active phosphorylation of specific targets in NHL cells. CX-4945 caused a dose-dependent growth-arresting effect on GCB, non-GCB DLBCL and BL cell-lines and it efficiently shut off phosphorylation of NF-?B RelA and CDC37 on CK2 target sites. Thus, CK2 is highly expressed and could represent a suitable therapeutic target in BL, FL and DLBCL NHL.
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Project description:Classifiers based on molecular criteria such as gene expression signatures have been developed to distinguish Burkitt lymphoma and diffuse large B cell lymphoma, which help to explore the intermediate cases where traditional diagnosis is difficult. Transfer of these research classifiers into a clinical setting is challenging because there are competing classifiers in the literature based on different methodology and gene sets with no clear best choice; classifiers based on one expression measurement platform may not transfer effectively to another; and, classifiers developed using fresh frozen samples may not work effectively with the commonly used and more convenient formalin fixed paraffin-embedded samples used in routine diagnosis.Here we thoroughly compared two published high profile classifiers developed on data from different Affymetrix array platforms and fresh-frozen tissue, examining their transferability and concordance. Based on this analysis, a new Burkitt and diffuse large B cell lymphoma classifier (BDC) was developed and employed on Illumina DASL data from our own paraffin-embedded samples, allowing comparison with the diagnosis made in a central haematopathology laboratory and evaluation of clinical relevance.We show that both previous classifiers can be recapitulated using very much smaller gene sets than originally employed, and that the classification result is closely dependent on the Burkitt lymphoma criteria applied in the training set. The BDC classification on our data exhibits high agreement (~95 %) with the original diagnosis. A simple outcome comparison in the patients presenting intermediate features on conventional criteria suggests that the cases classified as Burkitt lymphoma by BDC have worse response to standard diffuse large B cell lymphoma treatment than those classified as diffuse large B cell lymphoma.In this study, we comprehensively investigate two previous Burkitt lymphoma molecular classifiers, and implement a new gene expression classifier, BDC, that works effectively on paraffin-embedded samples and provides useful information for treatment decisions. The classifier is available as a free software package under the GNU public licence within the R statistical software environment through the link http://www.bioinformatics.leeds.ac.uk/labpages/softwares/ or on github https://github.com/Sharlene/BDC.
| S-EPMC4512160 | biostudies-literature
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common high-grade B-cell lymphoma found in Korea; it manifests with a variety of cellular morphologies and a high proliferation index. It is difficult to differentiate between DLBCL and Burkitt lymphoma (BL) based on immunohistochemistry, histology, and Epstein-Barr virus infection status owing to the overlap in findings. In this study, we performed comparative morphometric analysis to understand the proportional difference in Ki-67 staining between DLBCL and BL. We analyzed Ki-67-stained slides of 103 DLBCLs and 29 BLs that were pathologically confirmed using a three-tier classification system (negative, 1+, 2+, and 3+) to compare Ki-67 expression between BL and activated B-cell and germinal center B-cell subtypes of DLBCL and DLBCL with high proliferation indices (>90% of 2+ and 3+ cells). Patients with DLBCL were older than those with BL (62.1 versus 51.0 years). The number and proportion of negative cells (passenger and true negative cells) were significantly lower in BLs than those in DLBCLs (337.4, 5.9% versus 690.3, 12.4%). The number and proportion of 3+ cells were significantly higher in BLs than those in DLBCLs (5213.6, 96.3% versus 3132.4, 62.0%). BLs and DLBCLs with a high proliferation index showed similar results as those between BLs and overall DLBCLs. We were able to differentiate BLs and DLBCLs with 98.1% sensitivity and 100.0% specificity using an optimal cut-off of 97.9% of 2+/3+ Ki-67-positive cells. Thus, the Ki-67 labeling index may be a good differential biomarker for DLBCLs and BLs.
| S-EPMC7922648 | biostudies-literature
Project description:As part of the ICGC, the ICGC MMML-Seq project performed whole genome sequencing of a rare Burkitt lymphoma subtype with precursor B-cell immunophenotype. Analysis were performed in concordance with the guidelines of the ICGC.
| EGAS00001002968 | EGA
Project description:In this study we investigated to which extend aberrant c Myc activity plays a functional role in other aNHL and whether it is independent from MYC translocations. Based on a combined microarray analysis of human germinal centre (GC) B cells transfected with c Myc and 220 aNHLs cases, we developed a ‘c Myc index’. This data set contains expresssion profiles from Germinal center B-cells transfected with control or Myc expression vectors. The corresponding lymphoma gene expression profiles are included in the series with GEO accession GSE4475. Expression profiling of germinal center B-cells extracted from human tonsils with and without ectopic expression of Myc.
2011-11-01 | E-GEOD-31311 | biostudies-arrayexpress
Project description:Diffuse Large B-cell Lymphomas (DLBCL) are the most frequent Non-Hodgkin Lymphomas (NHL). The addition of Rituximab to the standard chemotherapy CHOP improved the outcome in this patients, but so far 40% of patients experienced relapse or progressive disease. Lenalidomide, an immunomodulatory agent, had direct tumoricidal and antiangiogenetic actions on tumor cells and was able to modulate tumor-cell microenvironment, with the restoration of impaired T-cell activity and the formation of immuno-synapsis. Based on these actions, lenalidomide represented an active drug on aggressive relapsed NHL. In this review, the most relevant clinical trials for the use of lenalidomide in DLBCL were reported. Monotherapy with lenalidomide showed an activity in term of overall response rate, with acceptable hematological and extrahematological toxicities in relapsed/refractory aggressive NHL. The role of lenalidomide as salvage therapy in both cell of origin patterns in DLBCL (germinal center B-cell/activated B-cell) was reported in preliminary data. Preliminary data regarding the role of lenalidomide in addition to chemoimmunotherapy (R-CHOP) in first line clinical trials were discussed; data of safety, feasibility and efficacy were promising.
| S-EPMC3390034 | biostudies-literature
Project description:Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-kappaB pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified. Here we report recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.
| S-EPMC2850970 | biostudies-literature
Project description:Intrinsic resistance of lymphoma cells to apoptosis is a probable mechanism causing chemotherapy resistance and eventual fatal outcome in patients with diffuse large B cell lymphomas (DLBCL). We investigated whether microarray expression profiling of apoptosis related genes predicts clinical outcome in 46 patients with primary nodal DLBCL. Unsupervised cluster analysis using genes involved in apoptosis (N=246) resulted in 3 separate DLBCL groups partly overlapping with GCB versus ABC like phenotype. One group with poor clinical outcome was characterized by high expression levels of pro-and anti-apoptotic genes involved in the intrinsic apoptosis pathway. A 2nd group, also with poor clinical outcome, was characterized by high levels of apoptosis inducing cytotoxic effector genes, possibly reflecting a cellular cytotoxic immune response. The 3rd group showing a favourable outcome was characterized by low expression levels of genes characteristic for both other groups. Our results suggest that chemotherapy refractory DLBCL are characterized either by an intense cellular cytotoxic immune response or by constitutive activation of the intrinsic mediated apoptosis pathway with concomitant downstream inhibition of this apoptosis pathway. Consequently, strategies neutralizing the function of apoptosis-inhibiting proteins might be effective as alternative treatment modality in part of chemotherapy refractory DLBCL. Keywords: expression profiling B lymphomas
2006-12-08 | GSE3892 | GEO
Project description:In this study we investigated to which extend aberrant c Myc activity plays a functional role in other aNHL and whether it is independent from MYC translocations. Based on a combined microarray analysis of human germinal centre (GC) B cells transfected with c Myc and 220 aNHLs cases, we developed a ‘c Myc index’. This data set contains expresssion profiles from Germinal center B-cells transfected with control or Myc expression vectors. The corresponding lymphoma gene expression profiles are included in the series with GEO accession GSE4475.
2011-11-01 | GSE31311 | GEO