FCGR2A and FCGR3A polymorphisms in classical Hodgkin lymphoma by Epstein-Barr virus status.
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ABSTRACT:
SUBMITTER: Ghesquieres H
PROVIDER: S-EPMC3999590 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAccumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification.MethodsWe conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided.ResultsTwo novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 × 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 × 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 × 10(-4)) and replication series (P = .03).ConclusionOverall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.
| S-EPMC3274508 | biostudies-literature
Project description:Transcriptional profiling of Human Hodkin Lymphoma lineages infected or not by Epstein Baar Virus (EBV). We compared EBV infected lineage L591 and not EBV infected lineages L428, L1236 and KMH2. Goal was to determine presence versus absence of EBV infection on global gene expression of Hodkin Lymphoma cell lines.
2011-12-31 | GSE21586 | GEO
Project description:Transcriptional profiling of Human Hodkin Lymphoma lineages infected or not by Epstein Baar Virus (EBV). We compared EBV infected lineage L591 and not EBV infected lineages L428, L1236 and KMH2. Goal was to determine presence versus absence of EBV infection on global gene expression of Hodkin Lymphoma cell lines. EBV infected Hodkin Lymphoma lineage L591 vs 3 Hodkin Lymphoma lineages not EBV infected L428, L1236 and KMH2. Dye Swap and direct comparisom between L591 (EBV infected) and the three others not infected cell lines.
2011-12-31 | E-GEOD-21586 | biostudies-arrayexpress
Project description:STAT3 is a transcription factor which is activated via various signaling transduction pathways or Epstein-Barr virus (EBV) infection and plays an oncogenic role in lymphoid malignancies including Hodgkin lymphoma (HL). The tumor cells of HL are derived from germinal center B-cells and transformed by chromosomal rearrangements, aberrant signal transduction, deregulation of developmental transcription factors, and EBV activity. HL cell lines represent useful models to investigate molecular principles and deduced treatment options of this malignancy. Using cell line L-540, we have recently shown that constitutively activated STAT3 drives aberrant expression of hematopoietic NKL homeobox gene HLX. Here, we analyzed HL cell line AM-HLH which is EBV-positive but, nevertheless, HLX-negative. Consistently, AM-HLH expressed decreased levels of STAT3 proteins which were additionally inactivated and located in the cytoplasm. Combined genomic and expression profiling data revealed several amplified and overexpressed gene candidates involved in opposed regulation of STAT3 and EBV. Corresponding knockdown studies demonstrated that IRF4 and NFATC2 inhibited STAT3 expression. MIR155 (activated by STAT3) and SPIB (repressed by HLX) showed reduced and elevated expression levels in AM-HLH, respectively. However, treatment with IL6 or IL27 activated STAT3, elevated expression of HLX and MIR155, and inhibited IRF4. Taken together, this cell line deals with two conflicting oncogenic drivers, namely, JAK2-STAT3 signaling and EBV infection, but is sensitive to switch after cytokine stimulation. Thus, AM-HLH represents a unique cell line model to study the pathogenic roles of STAT3 and EBV and their therapeutic implications in HL.
| S-EPMC9313380 | biostudies-literature
Project description:Hodgkin/Reed-Sternberg (HRS) cells in the setting of chronic lymphocytic leukemia (CLL) exist in 2 forms: type I with isolated HRS cells in a CLL background (Hodgkin-like lesion) and type II with typical classic Hodgkin lymphoma, a variant of Richter transformation (CHL-RT). The clinical significance of the 2 morphological patterns is unclear, and their biological features have not been compared. We retrospectively reviewed 77 cases: 26 of type I and 51 of type II CHL-RT; 3 cases progressed from type I to type II. We examined clinical features, Epstein-Barr virus (EBV) status, and clonal relatedness after microdissection. Median age for type I was 62 years versus 73 years for type II (P=.01); 27% (type I) versus 73% (type II) had a history of CLL. HRS cells were positive for EBV in 71% (55/77), similar in types I and II. Clonality analysis was performed in 33 cases (type I and type II combined): HRS cells were clonally related to the underlying CLL in 14 and unrelated in 19. ZAP-70 expression of the CLL cells but not EBV status or morphological pattern was correlated with clonal relatedness: all 14 clonally related cases were ZAP-70 negative, whereas 74% (14/19) of clonally unrelated cases were ZAP-70 positive. Overall median survival (types I and II) after diagnosis was 44 months. Advanced age was an adverse risk factor for survival, but not histologic pattern, type I versus type II. HRS-like cells in a background of CLL carries a similar clinical risk to that of CHL-RT and may progress to classic Hodgkin lymphoma in some cases.
| S-EPMC4981556 | biostudies-literature
Project description:Classical Hodgkin lymphoma (CHL) is a neoplasm characterized by robust inflammatory infiltrates and heightened expression of the immunosuppressive PD-1/PD-L1 pathway. Although anti-PD-1 therapy can be effective in >60% of patients with refractory CHL, improved treatment options are needed for CHLs which are resistant to anti-PD-1 or relapse after this form of immunotherapy. A deeper understanding of immunologic factors in the CHL microenvironment might support the design of more effective treatment combinations based on anti-PD-1. In addition, because the Epstein-Barr virus (EBV) residing in some CHL tumors is strongly immunogenic, we hypothesized that characteristics of the tumor immune microenvironment in EBV+ CHL would be distinct from EBV- CHL, with specific implications for designing combination treatment regimens. Employing immunohistochemistry for immune cell subsets and checkpoint molecules, as well as gene expression profiling, we characterized 32 CHLs from the Johns Hopkins archives, including 12 EBV+ and 20 EBV- tumors. Our results revealed a dichotomous cellular and cytokine immune milieu in EBV+ vs EBV- CHL. EBV+ tumors displayed a T helper 1 (Th1) profile typical of effective antitumor immunity, with increased infiltration of CD8+ T cells and coordinate expression of the canonical Th1 transcription factor Tbet (TBX21), interferon-γ (IFNG), and the IFN-γ-inducible immunosuppressive enzyme indoleamine 2,3-dioxygenase. In contrast, EBV- tumors manifested a pathogenic Th17 profile and ongoing engagement of the interleukin-23 (IL-23)/IL-17 axis, with heightened phosphorylated signal transducer and activator of transcription 3 expression in infiltrating lymphocytes. These findings suggest that drugs blocking the IL-23/IL-17 axis, which are already in the clinic for treating certain autoimmune disorders, may enhance the therapeutic impact of anti-PD-1 therapy in EBV- CHL.
| S-EPMC5727974 | biostudies-literature
Project description:Epstein-Barr virus (EBV) is associated with a variety of tumors and nonmalignant conditions. Latent EBV genomes in cells, including tumor cells, are often CpG methylated, whereas virion DNA is not CpG methylated. We demonstrate that methyl CpG binding magnetic beads can be used to fractionate among sources of EBV DNA (DNA extracted from laboratory-purified virions vs DNA extracted from latently infected cell lines). We then applied the technique to plasma specimens and showed that this technique can distinguish EBV DNA from patients with EBV-associated tumors (nasopharyngeal carcinoma, Hodgkin lymphoma) and viral DNA from patients without EBV-associated tumors, including immunocompromised patients and patients with EBV(-) Hodgkin lymphoma.
| S-EPMC7189298 | biostudies-literature
Project description:Background Epstein-Barr virus (EBV) glycoprotein 42 (gp42) enters B lymphocytes by binding to the human leukocyte antigen II (HLA-II) on their surface, in a process involving other EBV proteins (e.g., gH/gL and gp350). From a latent state of infection, the virus may reactivate and enter into a rapid proliferation phase, which enables the further entry of EBV into B lymphocytes and epithelial cells, leading to tumor development. EBV is an oncogenic virus associated with Hodgkin lymphoma (HL), and gp42 is a key protein in EBV infection of B lymphocytes. However, the exact binding pattern and capacity of gp42 are unclear. Methods The patterns and morphologies of gp42 binding to HLA-DPB1 were obtained through molecular dynamics simulation. The binding efficiency of gp42 and HLA-DPB1 was verified by plasmid construction and flow cytometry. Results The β-chain of HLA-DPB1 and the α-chain of gp42 formed a hydrogen-bonded complex, which was a hydrophilic protein with a resolution of 3.25. The binding efficiency between HLA-DPB1 and gp42 reached its peak (range, 26–31.3%) at a gp42 protein concentration of 80 µg. Conclusions We can inhibit the binding of gp42 to HLA-DPB1 by reducing the concentration of gp42. In the subsequent experiments, we will verify whether the binding of gp42 to HLA-DPB1 can be prevented by breaking hydrogen bonds and destroying hydrophilicity. These data may provide certain reference value for the development and treatment of Hodgkin’s lymphoma.
| S-EPMC8798132 | biostudies-literature
Project description:The pathogenesis of classical Hodgkin lymphoma (cHL) involves environmental and genetic factors. To explore the role of the human leukocyte antigen (HLA) genes, we performed a case-control genotyping study in 338 Dutch cHL patients using a PCR-based sequence-specific oligonucleotide probe (SSOP) hybridization approach. The allele frequencies were compared to HLA typings of more than 6,000 controls. The age of the cHL patients varied between 13 and 81 years with a median of 35 years. Nodular sclerosis subtype was the most common subtype (87%) and EBV was detected in 25% of the cHL patients. HLA-B5 was significantly increased and HLA-DR7 significantly decreased in the total cHL patient population as compared to controls. Two class II associations were observed to be specific for the EBV- cHL population with an increase of HLA-DR2 and HLA-DR5. Allele frequencies of HLA-A1, HLA-B37 and HLA-DR10 were significantly increased in the EBV+ cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in Caucasians. The allele frequency of HLA-A2 was significantly decreased in the EBV+ cHL population. Analysis of haplotypes with a frequency of >1% revealed a significant increase of HLA-A2-B7-DR2 in EBV- cHL as compared to controls. SSOP association analysis revealed significant differences between EBV+ and EBV- cHL patients for 19 probes that discriminate between HLA-A*01 and HLA-A*02. In conclusion, the HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV+ cHL. Furthermore several new protective and predisposing HLA class I and II associations for the EBV+, the EBV- and the entire cHL population were identified.
| S-EPMC3393726 | biostudies-literature
Project description:IntroductionEpstein-Barr virus (EBV) contributes significantly to the development and occurrence of B-cell lymphomas. However, the association between EBV infection status and clinical outcomes in Hodgkin lymphoma (HL) patients has long been controversial. Therefore, we aimed to estimate the prognostic significance of EBV infection in HL survival.MethodsWe searched PubMed, Embase, Web of Science, and the Cochrane Library for relevant cohort studies from the date of their inception to February 20, 2022. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS), Failure-free survival (FFS), Progression-free survival (PFS), Event-free survival (EFS) and disease-specific survival (DSS) were extracted from the studies or calculated. Subgroup analyses were conducted independently on the five survival outcomes to investigate the source of heterogeneity.ResultsA total of 42 qualified studies involving 9570 patients were identified in our meta-analysis. There was an association between EBV positivity and significantly poorer OS (HR=1.443, 95% CI: 1.250-1.666) and DSS (HR=2.312, 95% CI: 1.799-2.972). However, the presence of EBV in HL showed no effect on FFS, PFS or EFS. In subgroup analyses of OS, DSS and FFS stratified by age groups, EBV positivity was associated with poorer prognosis in elderly patients. Meanwhile, in children and adolescents with EBV-positive HL, we also observed a trend toward a better prognosis, though the results were not statistically significant.ConclusionsEBV-positive status is associated with poor OS and DSS in HL patients. EBV infection should therefore be considered a valuable prognostic marker and risk-stratifying factor in HL, especially in older patients.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022328708.
| S-EPMC9648611 | biostudies-literature