Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma
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PROVIDER: PRJNA555356 | ENA |
REPOSITORIES: ENA
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Project description:Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype-phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the JAK-STAT and NF-kB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, PDCD1LG2). Our analyses highlight the IRF-pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL as compared to diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relationship between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic work-up and therapeutic decision-making.
2019-09-18 | GSE134511 | GEO
Project description:Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype-phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the JAK-STAT and NF-kB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, PDCD1LG2). Our analyses highlight the IRF-pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL as compared to diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relationship between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic work-up and therapeutic decision-making.
| EGAS00001003746 | EGA
Project description:Diffuse large B-cell lymphoma (DLBCL) is currently divided into three main molecular subtypes, defined by gene expression profiling (GEP): Germinal Center B-cell like (GCB), Activated B-Cell like (ABC), and Primary Mediastinal B-cell Lymphoma (PMBL). DLBCL subtypes were determined according to patients' gene expression profiles.
2017-01-30 | GSE87371 | GEO
Project description:Primary mediastinal B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma. PMBCL has been previously studied with a variety of genomic techniques resulting in frequent detection of chromosomal gains; however, chromosomal losses have been rarely reported. This finding contrasts many other types of lymphoma, in which deletions are common. We hypothesize that segmental losses do exist but may have escaped detection by methods used in the previous studies. Using array comparative genomic hybridization to a tiling-resolution microarray encompassing the entire human genome, PMBCL samples were analyzed for genomic copy number alterations. Both gains and losses of chromosomal material were detected throughout the genome. These DNA copy number alterations were confirmed by quantitative real-time PCR. Recurrent chromosomal losses include a novel event at 1p13.1-p13.2 present in 42% of cases analyzed. We conclude that losses are present in the PMBCL genome. Given the similar frequency of losses to that of segmental gains of DNA, they are likely to play an important role in the pathogenesis of PMBCL. Keywords: array CGH, PMBCL
2007-08-15 | GSE7383 | GEO
Project description:Primary mediastinal large B-cell lymphoma is hallmarked by large-scale copy-neutral loss of heterozygosity
| PRJNA763590 | ENA
Project description:Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. It is unknown whether copy-neutral loss of heterozygosity (CN-LOH) contributes to the pathogenesis of this tumor. To get insight into the CN-LOH landscape of PMBL, we performed Single Nucleotide Polymorphism array (SNPa) analysis of two PMBL-derived cell lines and 33 primary tumors. The study uncovered large-scale CN-LOH lesions in both cell lines and 90.9% (30/33) of primary tumors. The latter cases showed 133 CN-LOH stretches of size >25Mb which affected up to 14 chromosomes per case (mean of 4.4). Involvement of chromosomal segments was predominant (81.2%), which, in a heterozygous diploid context, suggests the implication of B-cell specific crossover events. Further analysis indicated that the CN-LOH lesions were triggered by one or two consecutive molecular hits. Notably, CN-LOH segments were non-randomly clustered on chromosome 6p (60%), 15 (37.2%) and 17q (40%). Preliminary whole-exome sequencing data yielded coincidence of these lesions with mutations in MHC I and histon-related genes (6p21), B2M (15q15) and GNA13 (17q23), respectively. We hypothesize that CN-LOH-associated hits occurred early during lymphomagenesis, following mutagenesis but preceding genomic gains. Screening of the cohort of 2,658 cancer whole-genomes revealed that the CN-LOH landscape in PMBL is unique and distinguishes this tumor from other malignancies. Altogether, CN-LOH lesions rank as the most frequent genetic defect identified so far in this disease and the CN-LOH landscape suggest a hitherto undescribed mitotic recombinational driver. The aberrations affect the expression of key driver genes and functionally alternate genomic deletions which are infrequent in PMBL.
2021-09-16 | GSE184212 | GEO
Project description:Primary mediastinal B-cell lymphoma (PMBCL) is a distinct subtype of diffuse large B-cell lymphoma. PMBCL has been previously studied with a variety of genomic techniques resulting in frequent detection of chromosomal gains; however, chromosomal losses have been rarely reported. This finding contrasts many other types of lymphoma, in which deletions are common. We hypothesize that segmental losses do exist but may have escaped detection by methods used in the previous studies. Using array comparative genomic hybridization to a tiling-resolution microarray encompassing the entire human genome, PMBCL samples were analyzed for genomic copy number alterations. Both gains and losses of chromosomal material were detected throughout the genome. These DNA copy number alterations were confirmed by quantitative real-time PCR. Recurrent chromosomal losses include a novel event at 1p13.1-p13.2 present in 42% of cases analyzed. We conclude that losses are present in the PMBCL genome. Given the similar frequency of losses to that of segmental gains of DNA, they are likely to play an important role in the pathogenesis of PMBCL. Whole genome tiling path array CGH of 20 PMBCL tumor samples and one cell line was performed against male reference genomic DNA. Alterations were confirmed via DNA copy number quantitative real-time PCR
2007-08-15 | E-GEOD-7383 | biostudies-arrayexpress
Project description:Cell lines of mediastinal lymphomas, one each of primary mediastinal (thymic) large B cell lymphoma (PMBL), classic Hodgkin lymphoma (CHL), B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL, and T-cell lymphoma were treated with rituximab (RmAb), brentuximab vedotin (BV), ibrutinib (IBR), prednisone (PRED) or untreated (UT) for 48 hours. Flow cytometry for PD-L1 protein was performed, and differential expression (DE) analysis of mRNA and miRNA performed by RNAseq. B-cell lines exhibited 2- fold increase in PD-L1 protein (p<.05) with RmAb compared to UT. Others showed no effect of RmAb, however, the T-cell line showed 2-fold increase on treatment with BV (P<.05). DE performed by limma showed no genomic level changes. ANOVA analysis of PMBL treated with RmAb, however, showed physiologic level DE involving >3000 genes involving multiple pathways associated with cell death and survival, protein degradation, mRNA translation, mRNA degradation, immunologic functions, and PD-1/PD-L1 immunotherapy. In the B cell lines, DE of CD274 (PD-L1) was decreased or not significant. MiRNA DE showed upregulation of 7 miRNAs, including miR-155-5p.
2022-06-14 | GSE206130 | GEO
Project description:Disease-defining signatures in lymphomas, driven by intricate molecular mechanisms, have advanced molecular taxonomies, refined classification, and may guide clinical management; however, the role of these signatures in driving disease hallmarks including subtype-specific organotropism remains largely unexplored. Primary mediastinal large B-cell lymphoma (PMBCL) is an exemplary lymphoma characterized by disease manifestations in the thymic niche, unique genetic alterations and immune escape. Here, we identified IRF4-C99R mutations uniquely occurring in PMBCL through mutational meta-analysis of large-scale datasets. Our functional studies, integrating multi-omics approaches with genome editing in PMBCL cells, revealed that IRF4-C99R contributes to a differentiation block phenotype. Specifically, we showed that IRF4-C99R reduces its binding to the ISRE motif within PRDM1, which encodes a key transcriptional regulator of B-cell differentiation, resulting in decreased PRDM1 expression. Additionally, IRF4-C99R suppresses TNIK, a key IFNγ pathway regulator, by impairing ISRE motif binding, thereby reducing IFNγ signaling and increasing thymus and activation-regulated chemokine (TARC) expression, which drives TARC-mediated chemotaxis of T regulatory cells. We also revealed that IRF4-C99R upregulates Ephrin Type-B Receptor 1 (EPHB1) through non-canonical AICE motif binding, and showed that overexpression of EPHB1 in an immunocompetent syngeneic lymphoma model influenced organotropism to favor thymic localization, without affecting tumor burden in other organs. IRF4-C99R mutation-induced phenotypes were validated in primary PMBCL tissues using single-nuclei RNA sequencing, confirming that the molecular mechanisms observed in vitro align with the pathophysiology of PMBCL in patients. Together, these findings demonstrate how a single genetic mutation orchestrates the coordinated regulation of hallmark traits including thymus-specific tropism in PMBCL.
2025-07-25 | GSE294947 | GEO
Project description:Disease-defining signatures in lymphomas, driven by intricate molecular mechanisms, have advanced molecular taxonomies, refined classification, and may guide clinical management; however, the role of these signatures in driving disease hallmarks including subtype-specific organotropism remains largely unexplored. Primary mediastinal large B-cell lymphoma (PMBCL) is an exemplary lymphoma characterized by disease manifestations in the thymic niche, unique genetic alterations and immune escape. Here, we identified IRF4-C99R mutations uniquely occurring in PMBCL through mutational meta-analysis of large-scale datasets. Our functional studies, integrating multi-omics approaches with genome editing in PMBCL cells, revealed that IRF4-C99R contributes to a differentiation block phenotype. Specifically, we showed that IRF4-C99R reduces its binding to the ISRE motif within PRDM1, which encodes a key transcriptional regulator of B-cell differentiation, resulting in decreased PRDM1 expression. Additionally, IRF4-C99R suppresses TNIK, a key IFNγ pathway regulator, by impairing ISRE motif binding, thereby reducing IFNγ signaling and increasing thymus and activation-regulated chemokine (TARC) expression, which drives TARC-mediated chemotaxis of T regulatory cells. We also revealed that IRF4-C99R upregulates Ephrin Type-B Receptor 1 (EPHB1) through non-canonical AICE motif binding, and showed that overexpression of EPHB1 in an immunocompetent syngeneic lymphoma model influenced organotropism to favor thymic localization, without affecting tumor burden in other organs. IRF4-C99R mutation-induced phenotypes were validated in primary PMBCL tissues using single-nuclei RNA sequencing, confirming that the molecular mechanisms observed in vitro align with the pathophysiology of PMBCL in patients. Together, these findings demonstrate how a single genetic mutation orchestrates the coordinated regulation of hallmark traits including thymus-specific tropism in PMBCL.
2025-07-25 | GSE294946 | GEO