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Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling.

ABSTRACT: Burkitt lymphoma (BL) predominates in pediatric patients, whereas diffuse large B-cell lymphoma (DLBCL) is uncommon. In contrast to adults, BL and DLBCL are treated similarly in children and both entities have superior outcomes in children compared with adults. Gene expression profiling (GEP) and miRNA expression profiling clearly differentiated pediatric DLBCL from BL, forming distinct clusters regardless of patient age. However, pathway analysis of GEP data identified minor differences between corresponding pediatric and adult tumors. Predominance (6:1) of the germinal center B-cell subtype to activated B-cell subtype was found among pediatric DLBCL. Two cases were molecularly classified as primary mediastinal B-cell lymphoma. We observed frequent abnormalities in 8q24 in pediatric DLBCL, including MYC rearrangement in 31% (5 of 16) and gain or amplification in 50% (6 of 12) nonrearranged cases. MYC rearrangement was present in 96% (23 of 24) BL cases. Array-based CGH analysis identified abnormalities that are shared between adult and pediatric DLBCL (+12q15, +19q13, -6q), and abnormalities unique to the pediatric cases (-4p14, -19q13.32, +16p11.2), suggesting distinct pathogenetic mechanisms relative to age. Elucidation of the underlying target genes may provide insight into factors that modulate outcome and could provide potential novel therapeutic targets with less toxicity for pediatric patients with B-cell non-Hodgkin lymphoma.

SUBMITTER: Deffenbacher KE

PROVIDER: S-EPMC3335381 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling.

Deffenbacher Karen E KE Iqbal Javeed J Sanger Warren W Shen Yulei Y Lachel Cynthia C Liu Zhongfeng Z Liu Yanyan Y Lim Megan S MS Perkins Sherrie L SL Fu Kai K Smith Lynette L Lynch James J Staudt Louis M LM Rimsza Lisa M LM Jaffe Elaine E Rosenwald Andreas A Ott German K GK Delabie Jan J Campo Elias E Gascoyne Randy D RD Cairo Mitchell S MS Weisenburger Dennis D DD Greiner Timothy C TC Gross Thomas G TG Chan Wing C WC

Blood 20120228 16

Burkitt lymphoma (BL) predominates in pediatric patients, whereas diffuse large B-cell lymphoma (DLBCL) is uncommon. In contrast to adults, BL and DLBCL are treated similarly in children and both entities have superior outcomes in children compared with adults. Gene expression profiling (GEP) and miRNA expression profiling clearly differentiated pediatric DLBCL from BL, forming distinct clusters regardless of patient age. However, pathway analysis of GEP data identified minor differences between ...[more]

PMID: 22374697

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Project description:We have previously reported a novel constitutively overexpressed 21 kDa protein in Hodgkin Lymphoma (HL) and aggressive Non-Hodgkin Lymphomas (NHL). The objective of the current study was to 1) identify this protein using two independent methods, 2) study the expression of the protein and its encoding mRNA in reactive lymph nodes, normal lymphocytes and CD34+ bone marrow precursor cells, 3) analyse patterns of expression of the protein in tissue microarrays assembled from a large number of diagnostic clinical biopsies from patients with HL, and 4) determine the copy number variation and mutation status of the encoding gene in HL cell lines.Peptide sequencing by LC-MS/MS and protein identification by protein array screening identified a single protein, CYB5B. No mutations were detected in the CYB5B gene in HL cell lines. Quantitative PCR showed CYB5B gene expression was increased in HL and NHL cell lines. Array CGH using a submegabase resolution tiling array revealed gains in the CYB5B locus in HL cell lines KMH2 and L428. Membrane expression was seen in Reed-Sternberg cells in clinical biopsies from patients with HL but not in reactive lymph nodes. Bone marrow CD34+ precursor cells were CYB5B negative on the cell surface. RT-PCR assays of RNA extracted from T and B cell enriched fractions obtained from normal peripheral blood mononuclear cells, reactive lymph nodes, tonsils and normal bone marrow samples showed no evidence of increased mRNA levels of CYB5B in comparison to housekeeping gene GAPDH.The 21 kDa protein overexpressed in HL and aggressive NHL is identical to CYB5B. CYB5B gene expression is increased in a subset of HL and NHL cell lines tested. This is associated with CYB5B gene amplification in HL cell lines KMH2 and L428. CYB5B may be a potential target for antibody-based therapy of HL and aggressive NHL as although cytoplasmic expression is present in reactive lymphocytes, it is not expressed on the cell surface of non-neoplastic lymphocytes or bone marrow precursor cells.

Project description:ObjectivesRituximab is a valuable agent for treating adult B-cell non-Hodgkin lymphoma (B-NHL), and several studies have tested its efficacy in children with mature, high-grade B-NHL. The aim of the present study was to systematically review the use of rituximab in children and adolescents with high-grade mature B-NHL and to conduct a meta-analysis of the evidence. Since access to this medication in public health systems in low- and middle-income countries is complex, we were also interested in mapping access to it in Brazil.MethodsWe conducted a systematic review and meta-analysis on the survival of pediatric patients with mature, high-grade and advanced-stage B-NHL treated with rituximab in combination with chemotherapy in first-line treatment or later. Patients' access to the medication was evaluated through a questionnaire sent to oncologists in Brazilian pediatric oncology centers.ResultsWe selected 17 trials, which were subsequently grouped by disease type and line of therapy. In patients receiving first-line treatment, excluding those with primary mediastinal B-cell lymphoma (PMBL), the use of rituximab resulted in (1) better event-free survival [Hazard Ratio of 0.37 (0.22, 0.61); p < 0.01]; (2) a reduced risk of events [odds ratio of 0.44 (0.26-0.76); p = 0.003]; and (3) a reduced risk of death [odds ratio of 0.44 (0.21-0.89); p = 0.02]. In refractory or relapsed (R/R) patients, rituximab use was associated with a decreased chance of death [odds ratio of 0.25 (0.09-0.75); p = 0.01]. Additionally, our survey included 31 Brazilian centers, 63% of which reported bearing the cost of rituximab.ConclusionRituximab improves outcomes in pediatric patients receiving first-line treatment for high-grade B-NHL (except PBML) and overall survival in R/R patients. However, access to rituximab in Brazilian hospitals is currently dependent on centers supporting its economic burden.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, PROSPERO (CRD42021292912).

Dataset Information

Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling.

Publications

Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling.

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