Detection of clinically relevant genetic and transcriptomic landscape in DLBCL uniformly treated by R-CHOP
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PROVIDER: EGAS00001002657 | EGA |
REPOSITORIES: EGA
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Project description:Recent studies using next-generation sequencing strategies have described the landscape of genetic alterations in diffuse large B-cell lymphoma (DLBCL). However, little is known about the clinical relevance of recurrent mutations and copy number alterations and their transcriptional footprints. This study examines the frequency, interaction and clinical impact of recurrent genetic aberrations in DLBCL using high-resolution technologies in a large population-based cohort.
| EGAD00001003783 | EGA
Project description:Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations that may contribute to their heterogeneous behavior. However, their clinical relevance and potential interest in identifying appropriate candidate drugs for personalized management are not well known. In this study, targeted next generation sequencing and genomic copy number alterations (CNA) were analyzed in 150 cases of diffuse large B-cell lymphoma (DLBCL) to define the clinical significance of recurrent genomic alterations and to identify potential targets for personalized management. An independent cohort of 111 patients was also analyzed to confirm the clinically significant findings. We found a differential profile of mutations, altered pathogenic pathways and CNA in germinal center B (GCB) and activated B-cell (ABC)-DLBCL with some shared alterations in both subtypes. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis that was independent of other parameters and confirmed in the validation cohort. Tumors with NOTCH pathway mutations had a significant overexpression of downstream target genes, emphasizing the relevance of this pathway in DLBCL. We identified other new relevant genes including TMEM30A, RHOA, EBF, and TOX, among others. In silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials (n=66) or pre-clinical assays (n=3) in DLBCL or other lymphomas. These findings orient future preclinical and clinical intervention strategies in DLBCL.
2018-03-14 | GSE94705 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients. 21 DLBCL cell lines and 70 DLBCL patient samples.
2013-01-23 | E-GEOD-43606 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma in adults. The disease exhibits a striking heterogeneity in gene expression profiles and clinical outcomes, but its genetic causes remain to be fully defined. Through whole genome and exome sequencing, we characterized the genetic diversity of DLBCL. In all, we sequenced 73 DLBCL primary tumors (34 with matched normal DNA). Separately, we sequenced the exomes of 21 DLBCL cell lines. We identified 322 DLBCL cancer genes that were recurrently mutated in primary DLBCLs. We identified recurrent mutations implicating a number of known and not previously identified genes and pathways in DLBCL including those related to chromatin modification (ARID1A and MEF2B), NF-κB (CARD11 and TNFAIP3), PI3 kinase (PIK3CD, PIK3R1, and MTOR), B-cell lineage (IRF8, POU2F2, and GNA13), and WNT signaling (WIF1). We also experimentally validated a mutation in PIK3CD, a gene not previously implicated in lymphomas. The patterns of mutation demonstrated a classic long tail distribution with substantial variation of mutated genes from patient to patient and also between published studies. Thus, our study reveals the tremendous genetic heterogeneity that underlies lymphomas and highlights the need for personalized medicine approaches to treating these patients.
2013-01-23 | GSE43606 | GEO
Project description:Copy number analysis can be useful for assessing prognosis in diffuse large B cell lymphoma (DLBCL). We analyzed copy number data from tumor samples of 60 patients diagnosed with DLBCL de novo and their matched normal samples. We detected a total of 63 recurrent copy number alterations (CNAs), including 33 gains, 30 losses, and nine recurrent acquired copy number neutral loss of heterozygosity (CNN-LOH). Interestingly, 20% of cases acquired CNN-LOH of 6p21 locus, which involves the HLA region. In normal cells there were no CNAs but we observed CNN-LOH involving some key lymphoma regions such as 6p21 and 9p24.1 (5%) and 17p13.1 (2.5%) in DLBCL patients. Furthermore, a model with some specific CNA was able to predict the subtype of DLBCL, 1p36.32 and 10q23.31 losses being restricted to germinal center B cell-like (GCB) DLBCL. In contrast, 8p23.3 losses and 11q24.3 gains were strongly associated with the non-GCB subtype. A poor prognosis was associated with biallelic inactivation of TP53 or 18p11.32 losses, while prognosis was better in cases carrying 11q24.3 gains, which includes ETS1 and FLI1 genes. In summary, CNA abnormalities identify specific DLBCL groups, and we describe CN-LOH in germline cells from DLBCL patients that are associated with genes that probably play a key role in DLBCL development.
2016-01-22 | GSE71389 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using highly-sensitive transcriptome profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of “unfavorable” molecular signatures.
2021-09-01 | GSE178965 | GEO
Project description:We performed array comparative genomic hybridization (aCGH) and gene expression profiling in 203 samples of diffuse large B cell lymphoma (DLBCL). By gene expression, at least three molecular subtypes of DLBCL termed as germinal center B cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, and primary mediastinal B cell lymphoma (PMBL) can be distinguished. Combining gene expression profiling and aCGH, revealed copy number abnormalities that had strikingly different frequencies in the three molecular DLBCL subtypes. These data provide genetic evidence that the DLBCL subtypes are distinct diseases that utilize different oncogenic pathways. Keywords: clinical history design The retrospective study included RNA and DNA extracted from 203 clinical samples.
2008-09-04 | E-GEOD-11318 | biostudies-arrayexpress
Project description:Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of malignant lymphoma and is heterogeneous with respect to morphology, biology, and clinical presentation.However, a robust prognostic factor based on cell biology of DLBCL has not yet been determined.To find the biomarker which may associate with clinical outcome in patients with DLBCL, microarray analysis was performed to screen a novel biomarker.
2021-03-26 | GSE128852 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using highly-sensitive transcriptome profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of “unfavorable” molecular signatures.
2021-06-18 | GSE178394 | GEO
Project description:Genomic profiles of DLBCL (Diffuse Large B-cell Lymphoma) patients 20 DLBCL patients were selected for detection of genomic aberrations
2009-12-16 | GSE19459 | GEO