Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromosome 12q24.1 is a recurrent breakpoint in high-grade B-cell non-Hodgkin lymphoma (B-NHL). To identify the genes involved at 12q24.1, molecular cloning of a three-way translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line (Wien 133) was performed; all four translocation breakpoints were cloned and sequenced. Analysis of clones encompassing the der(12)(12;14)(q24.1;q32.3) breakpoint showed a CpG island from chromosome 12q24.1 juxtaposed in a tail-to-tail configuration with a productively rearranged Ig VH4-DH-JH5 gene. A total of 4.5 kb of genomic DNA including the CpG island was sequenced and analyzed using gene-identification programs; all three programs identified a potential 92-bp exon within the centromeric boundary of the CpG island. Using this as a probe, an RNA transcript of 3.8 kb, expressed at low levels in a wide variety of normal tissues, was detected. Overlapping cDNA clones were isolated and sequenced. The longest open-reading frame predicted a serine-rich protein of 231 amino acids. This protein, termed BCL7A, exhibited no recognizable protein motifs but showed homology with the actin-binding protein, caldesmon. In Wien 133, the BCL7A breakpoint occurred within the first intron and resulted in a MYC-BCL7A fusion transcript, with exon I of BCL7A being replaced by MYC exon I. The normal, untranslocated allele of BCL7A was also expressed without mutation. One of the 11 other B-NHL cell lines examined with 12q24.1 cytogenetic abnormalities, a mediastinal B-NHL cell line (Karpas 1106), showed biallelic rearrangement within the first intron of BCL7A, which was adjacent to the breakpoint observed in Wien 133. Disruption of the amino-terminus of BCL7A defines a new mechanism in the pathogenesis of a subset of high-grade B-NHL.
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PMID:Molecular cloning of complex chromosomal translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line defines a new gene (BCL7A) with homology to caldesmon. 860 26

B-cell post-transplant lymphoproliferative disorders (PTLD) are classified as early lesions, polymorphic lymphomas (P-PTLD) and monomorphic lymphomas (M-PTLD). These morphologic categories are thought to reflect a biologic continuum, although supporting genetic data are lacking. To gain better insights into PTLD pathogenesis, we characterized the phenotypes, immunoglobulin (Ig) gene alterations and non-Ig gene (BCL6, RhoH/TTF, c-MYC, PAX5, CIITA, BCL7A, PIM1) mutations of 21 PTLD, including an IM-like lesion, 8 P-PTLD and 12 M-PTLD. Gene expression profile analysis was also performed in 12 cases. All PTLD with clonal Ig rearrangements showed evidence of germinal centre (GC) transit based on the analysis of Ig and BCL6 gene mutations, and 74% had a non-GC phenotype (BCL6 +/- MUM1+). Although surface Ig abnormalities were seen in 6/19 (32%) PTLD, only three showed 'crippling' Ig mutations indicating other etiologies for loss of the B-cell receptor. Aberrant somatic hypermutation (ASHM) was almost exclusively observed in M-PTLD (8/12 vs. 1/8 P-PTLD) and all three recurrent cases analysed showed additional mutations in genes targeted by ASHM. Gene expression analysis showed distinct clustering of PTLD compared to B-cell non-Hodgkin lymphomas (B-NHL) without segregation of P-PTLD from non-GC M-PTLD or EBV+ from EBV- PTLD. The gene expression pattern of PTLD appeared more related to that of memory and activated B-cells. Together, our results suggest that PTLD represent a distinct type of B-NHL deriving from an antigen experienced B-cell, whose evolution is associated with accrual of genetic lesions.
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PMID:Genetic and phenotypic analysis of B-cell post-transplant lymphoproliferative disorders provides insights into disease biology. 1845 40

Chromosomal translocations are the hallmark genetic aberration in non-Hodgkin lymphoma (NHL), with specific translocations often selectively associated with specific NHL subtypes. Because many NHL-associated translocations involve cell cycle, apoptosis, and lymphocyte development regulatory genes, we evaluated NHL risk associated with common genetic variation in 20 candidate genes in these pathways. Genotyping of 203 tag single nucleotide polymorphisms (SNP) was conducted in 1,946 NHL cases and 1,808 controls pooled from 3 independent population-based case-control studies. We used logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. We observed the most striking associations for tag SNPs in the proapoptotic gene BCL2L11 (BIM) and BCL7A, which is involved in a rare NHL-associated translocation. Variants in BCL2L11 were strongly related to follicular lymphoma only, particularly rs3789068 (OR(AG), 1.41; 95% CI, 1.10-1.81; OR(GG), 1.65; 95% CI, 1.25-2.19; P(trend) = 0.0004). Variants in BCL7A were strongly related to diffuse large B-cell lymphoma only, particularly rs1880030 (OR(AG), 1.34; 95% CI, 1.08-1.68; OR(AA), 1.60; 95% CI, 1.22-2.08; P(trend) = 0.0004). The associations for both variants were similar in all three studies and supported by haplotype analyses. We also observed notable associations for variants in BCL6, CCND1, and MYC. Our results support the role of common genetic variation in cell cycle, apoptosis, and lymphocyte development regulatory genes in lymphomagenesis, and suggest that effects may vary by NHL subtype. Replication of our findings and further study to identify functional SNPs are warranted.
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PMID:Risk of non-Hodgkin lymphoma associated with germline variation in genes that regulate the cell cycle, apoptosis, and lymphocyte development. 1933 52