Hodgkin Lymphoma - Molecular Biology

Overview

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • SH2D1A protein, human
  • Nuclear Proteins
  • inosine monophosphate synthase
  • Viral Matrix Proteins
  • Tumor Virus Infections
  • Lymphocytes
  • Oligonucleotide Array Sequence Analysis
  • Lymph Nodes
  • Molecular Sequence Data
  • Non-Hodgkin Lymphoma
  • DNA-Binding Proteins
  • BCL11A
  • DNA Methylation
  • Adolescents
  • Diffuse Large B-Cell Lymphoma
  • B-Lymphocytes
  • CD Antigens
  • Gene Expression Profiling
  • Immunoglobulin Heavy Chains
  • DNA Sequence Analysis
  • FISH
  • Genetic Predisposition
  • Childhood Cancer
  • Immunohistochemistry
  • Hodgkin Lymphoma
  • Protein Kinases
  • NF-kappa B
  • Nucleic Acid Hybridization
  • Case-Control Studies
  • DNA Mutational Analysis
  • Alleles
  • Herpesvirus 4, Human
  • Apoptosis
  • RTPCR
  • Epstein-Barr Virus Infections
  • Genotype
  • BCL3
  • B-Cell Lymphoma
  • Cancer Gene Expression Regulation
  • Chromosome Aberrations
  • Neoplasm Proteins
  • CDKN2A
  • Base Sequence
  • Cancer DNA
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (31)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
TNFRSF8 1p36 CD30, Ki-1, D1S166E -TNFRSF8 and Hodgkin Lymphoma
96
REL 2p13-p12 C-Rel -REL and Hodgkin Lymphoma
22
IL13 5q31 P600, IL-13 -IL13 and Hodgkin Lymphoma
13
CD68 17p13 GP110, LAMP4, SCARD1 -CD68 and Hodgkin Lymphoma
13
CD79A 19q13.2 IGA, MB-1 -CD79A and Hodgkin Lymphoma
13
STAT6 12q13 STAT6B, STAT6C, D12S1644, IL-4-STAT -STAT6 and Hodgkin Lymphoma
11
CDKN2A 9p21 ARF, MLM, P14, P16, P19, CMM2, INK4, MTS1, TP16, CDK4I, CDKN2, INK4A, MTS-1, P14ARF, P19ARF, P16INK4, P16INK4A, P16-INK4A -CDKN2A Expression in Hodgkin's Disease
11
HLA-DPB1 6p21.3 DPB1, HLA-DP, HLA-DPB, HLA-DP1B -HLA-DPB1 and Hodgkin Lymphoma
9
CD79B 17q23 B29, IGB, AGM6 -CD79B and Hodgkin Lymphoma
8
IRF4 6p25-p23 MUM1, LSIRF, SHEP8, NF-EM5 -IRF4 and Hodgkin Lymphoma
8
TNFAIP3 6q23 A20, OTUD7C, TNFA1P2 -TNFAIP3 and Hodgkin Lymphoma
7
NFKBIA 14q13 IKBA, MAD-3, NFKBI -NFKBIA and Hodgkin Lymphoma
7
BCL11A 2p16.1 EVI9, CTIP1, ZNF856, HBFQTL5, BCL11A-L, BCL11A-S, BCL11a-M, BCL11A-XL -BCL11A and Hodgkin Lymphoma
6
CD274 9p24 B7-H, B7H1, PDL1, PD-L1, PDCD1L1, PDCD1LG1 -CD274 and Hodgkin Lymphoma
6
BCL3 19q13.1-q13.2 BCL4, D19S37 -BCL3 and Hodgkin Lymphoma
6
CCL17 16q13 TARC, ABCD-2, SCYA17, A-152E5.3 -CCL17 and Hodgkin Lymphoma
6
POU2AF1 11q23.1 BOB1, OBF1, OCAB, OBF-1 -POU2AF1 and Hodgkin Lymphoma
5
TIA1 2p13 WDM, TIA-1 -TIA1 and Hodgkin Lymphoma
5
CCL22 16q13 MDC, ABCD-1, SCYA22, STCP-1, DC/B-CK, A-152E5.1 -CCL22 and Hodgkin Lymphoma
4
TRAF3 14q32.32 CAP1, LAP1, CAP-1, CRAF1, IIAE5, CD40bp -TRAF3 and Hodgkin Lymphoma
4
PDCD1LG2 9p24.2 B7DC, Btdc, PDL2, CD273, PD-L2, PDCD1L2, bA574F11.2 -PDCD1LG2 and Hodgkin Lymphoma
3
POU2F2 19q13.2 OCT2, OTF2, Oct-2 -POU2F2 and Hodgkin Lymphoma
3
IL13RA1 Xq24 NR4, CD213A1, IL-13Ra -IL13RA1 and Hodgkin Lymphoma
3
CD163 12p13.3 M130, MM130 -CD163 and Hodgkin Lymphoma
3
ATIC 2q35 PURH, AICAR, AICARFT, IMPCHASE, HEL-S-70p -ATIC and Hodgkin Lymphoma
2
DDR2 1q23.3 TKT, MIG20a, NTRKR3, TYRO10 -DDR2 and Hodgkin Lymphoma
2
PTPN1 20q13.1-q13.2 PTP1B -PTPN1 mutations in Hodgkin Lymphoma and PMBCL
2
SH2D1A Xq25 LYP, SAP, XLP, DSHP, EBVS, IMD5, XLPD, MTCP1, XLPD1, SAP/SH2D1A -SH2D1A and Hodgkin Lymphoma
2
IL4R 16p12.1-p11.2 CD124, IL4RA, IL-4RA -IL4R and Hodgkin Lymphoma
2
TBX21 17q21.32 TBET, T-PET, T-bet, TBLYM -TBX21 and Hodgkin Lymphoma
2
FUT4 11q21 LeX, CD15, ELFT, FCT3A, FUTIV, SSEA-1, FUC-TIV -FUT4 and Hodgkin Lymphoma
2

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Oki Y, Neelapu SS, Fanale M, et al.
Detection of classical Hodgkin lymphoma specific sequence in peripheral blood using a next-generation sequencing approach.
Br J Haematol. 2015; 169(5):689-93 [PubMed] Related Publications
We applied a highly sensitive next-generation sequencing method to identify lymphoma-specific immunoglobulin gene segments in classical Hodgkin lymphoma (CHL) at initial diagnosis or recurrence, and assessed the ability of detecting such lymphoma-specific sequences in peripheral blood (PB). Seventeen CHL cases were tested and lymphoma-specific sequences were identified in 12 of the primary tumour biopsies. In 11 of these patients whose paired PB samples were available, tumour-specific clonotypes were detected in PB in eight patients. This data demonstrates the feasibility of detecting circulating tumour-specific sequences, creating an unprecedented opportunity to optimize the future treatment and monitoring strategies for patients with CHL.

Hartmann S, Döring C, Vucic E, et al.
Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma.
Br J Haematol. 2015; 169(3):415-22 [PubMed] Related Publications
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte rich large B cell lymphoma (THRLBCL) usually affect middle-aged men, show tumour cells with a B cell phenotype and a low tumour cell content. Whereas the clinical behaviour of NLPHL is indolent, THRLBCL presents with advanced stage disease and an aggressive behaviour. In the present study, array comparative genomic hybridization was performed in seven typical NLPHL, four THRLBCL-like NLPHL variants, six THRLBCL and four diffuse large B cell lymphomas (DLBCL) derived from NLPHL. The number of genomic aberrations was higher in THRLBCL compared with typical and THRLBCL-like variant of NLPHL. Gains of 2p16.1 and losses of 2p11.2 and 9p11.2 were commonly observed in typical and THRLBCL-like variants of NLPHL as well as THRLBCL. Gains of 2p16.1, affecting the REL locus were confirmed in an independent cohort. Expression of the REL protein was observed at similar frequencies in typical and THRLBCL-like variant of NLPHL as well as THRLBCL (33-38%). In conclusion, the present study reveals further similarities between NLPHL and THRLBCL on the genomic level, confirming that these entities are part of a pathobiological spectrum with common molecular features, but varying clinical presentations.

Bond DA, Dunavin N, Otterson GA
Mutational profiling of second primary lung cancers in patients who have received radiation for the treatment of Hodgkin's disease.
Cancer Invest. 2015; 33(3):86-8 [PubMed] Related Publications
Lung cancer (LC) represents the most common solid tumor in survivors of Hodgkin's disease (HD), and the assessment of the mutational status of oncogenic driver mutations in LC is now standard. We compiled clinical and mutation data (EGFR, KRAS, and ALK) from the medical records of patients with LC and a remote history of HD. 13 cases of LC following HD were seen, including seven with mutational data. Two had EGFR mutations, none had KRAS mutations or ALK translocations. Our conclusions are limited by the small sample size, however this report reinforces the need to identify driver mutations in lung cancers.

Reichel J, Chadburn A, Rubinstein PG, et al.
Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells.
Blood. 2015; 125(7):1061-72 [PubMed] Related Publications
Classical Hodgkin lymphoma (cHL) is characterized by sparsely distributed Hodgkin and Reed-Sternberg (HRS) cells amid reactive host background, complicating the acquisition of neoplastic DNA without extensive background contamination. We overcame this limitation by using flow-sorted HRS and intratumor T cells and optimized low-input exome sequencing of 10 patient samples to reveal alterations in genes involved in antigen presentation, chromosome integrity, transcriptional regulation, and ubiquitination. β-2-microglobulin (B2M) is the most commonly altered gene in HRS cells, with 7 of 10 cases having inactivating mutations that lead to loss of major histocompatibility complex class I (MHC-I) expression. Enforced wild-type B2M expression in a cHL cell line restored MHC-I expression. In an extended cohort of 145 patients, the absence of B2M protein in the HRS cells was associated with lower stage of disease, younger age at diagnosis, and better overall and progression-free survival. B2M-deficient cases encompassed most of the nodular sclerosis subtype cases and only a minority of mixed cellularity cases, suggesting that B2M deficiency determines the tumor microenvironment and may define a major subset of cHL that has more uniform clinical and morphologic features. In addition, we report previously unknown genetic alterations that may render selected patients sensitive to specific targeted therapies.

Ben Dhiab M, Ziadi S, Ksiaa F, et al.
Methylation of miR124a-1, miR124a-2, and miR124a-3 in Hodgkin lymphoma.
Tumour Biol. 2015; 36(3):1963-71 [PubMed] Related Publications
Deregulation of the microRNA miR124a by DNA methylation has been implicated in various malignancies, but no study reported its methylation status in Hodgkin lymphoma (HL). We evaluated the methylation of the three loci encoding for miR124a using methylation-specific PCR in 64 HL patients and 15 reactive lymph nodes obtained from patients with nonmalignant diseases. Results were correlated with clinicopathological parameters. Methylation rates of miR124a-1, miR124a-2, and miR124a-3 in HL were 17, 50, and 28%, respectively. None of the nontumoral samples showed aberrant hypermethylation in any of the miR tested. In HL cases, we found that miR124a-1 methylation correlates with high-risk International Prognostic Score (IPS) (score >3, p = 0.04) and that miR124a-2 methylation was more frequent in children (82.3%, p = 0.006) and men (63.9%, p = 0.01). Methylation of miR124a-3 was associated with advanced Ann-Arbor stages (p = 0.007). The survival analysis showed that methylation of at least one of the miR124a genes was associated with shortened event-free survival in univariate (p = 0.03) and multivariate (p = 0.02) analyses. These results suggest that miR124a methylation is associated with aggressive HL disease and may be an interesting factor for predicting treatment response.

Kreher S, Bouhlel MA, Cauchy P, et al.
Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma.
Proc Natl Acad Sci U S A. 2014; 111(42):E4513-22 [PubMed] Free Access to Full Article Related Publications
Deregulated transcription factor (TF) activities are commonly observed in hematopoietic malignancies. Understanding tumorigenesis therefore requires determining the function and hierarchical role of individual TFs. To identify TFs central to lymphomagenesis, we identified lymphoma type-specific accessible chromatin by global mapping of DNaseI hypersensitive sites and analyzed enriched TF-binding motifs in these regions. Applying this unbiased approach to classical Hodgkin lymphoma (HL), a common B-cell-derived lymphoma with a complex pattern of deregulated TFs, we discovered interferon regulatory factor (IRF) sites among the top enriched motifs. High-level expression of the proinflammatory TF IRF5 was specific to HL cells and crucial for their survival. Furthermore, IRF5 initiated a regulatory cascade in human non-Hodgkin B-cell lines and primary murine B cells by inducing the TF AP-1 and cooperating with NF-κB to activate essential characteristic features of HL. Our strategy efficiently identified a lymphoma type-specific key regulator and uncovered a tumor promoting role of IRF5.

Vera-Lozada G, Scholl V, Barros MH, et al.
Analysis of biological and technical variability in gene expression assays from formalin-fixed paraffin-embedded classical Hodgkin lymphomas.
Exp Mol Pathol. 2014; 97(3):433-9 [PubMed] Related Publications
Formalin-fixed paraffin-embedded (FFPE) tissues are invaluable sources of biological material for research and diagnostic purposes. In this study, we aimed to identify biological and technical variability in RT-qPCR TaqMan® assays performed with FFPE-RNA from lymph nodes of classical Hodgkin lymphoma samples. An ANOVA-nested 6-level design was employed to evaluate BCL2, CASP3, IRF4, LYZ and STAT1 gene expression. The most variable genes were CASP3 (low expression) and LYZ (high expression). Total variability decreased after normalization for all genes, except by LYZ. Genes with moderate and low expression were identified and suffered more the effects of the technical manipulation than high-expression genes. Pre-amplification was shown to introduce significant technical variability, which was partially alleviated by lowering to a half the amount of input RNA. Ct and Cy0 quantification methods, based on cycle-threshold and the kinetic of amplification curves, respectively, were compared. Cy0 method resulted in higher quantification values, leading to the decrease of total variability in CASP3 and LYZ genes. The mean individual noise was 0.45 (0.31 to 0.61 SD), indicating a variation of gene expression over ~1.5 folds from one case to another. We showed that total variability in RT-qPCR from FFPE-RNA is not higher than that reported for fresh complex tissues, and identified gene-, and expression level-sources of biological and technical variability, which can allow better strategies for designing RT-qPCR assays from highly degraded and inhibited samples.

Vogel MJ, Xie L, Guan H, et al.
FOXO1 repression contributes to block of plasma cell differentiation in classical Hodgkin lymphoma.
Blood. 2014; 124(20):3118-29 [PubMed] Related Publications
The survival of classical Hodgkin lymphoma (cHL) cells depends on activation of NF-κB, JAK/STAT, and IRF4. Whereas these factors typically induce the master regulator of plasma cell (PC) differentiation PRDM1/BLIMP-1, levels of PRDM1 remain low in cHL. FOXO1, playing a critical role in normal B-cell development, acts as a tumor suppressor in cHL, but has never been associated with induction of PC differentiation. Here we show that FOXO1 directly upregulates the full-length isoform PRDM1α in cHL cell lines. We also observed a positive correlation between FOXO1 and PRDM1 expression levels in primary Hodgkin-Reed-Sternberg cells. Further, we show that PRDM1α acts as a tumor suppressor in cHL at least partially by blocking MYC. Here we provide a link between FOXO1 repression and PRDM1α downregulation in cHL and identify PRDM1α as a tumor suppressor in cHL. The data support a potential role for FOXO transcription factors in normal PC differentiation.

Nagel S, Meyer C, Kaufmann M, et al.
Deregulated FOX genes in Hodgkin lymphoma.
Genes Chromosomes Cancer. 2014; 53(11):917-33 [PubMed] Related Publications
FOX genes encode transcription factors which regulate basic developmental processes during embryogenesis and in the adult. Several FOX genes show deregulated expression in particular malignancies, representing oncogenes or tumor suppressors. Here, we screened six Hodgkin lymphoma (HL) cell lines for FOX gene activity by comparative microarray profiling, revealing overexpression of FOXC1 and FOXD1, and reduced transcription of FOXN3, FOXO1, and FOXP1. In silico expression analyses of these FOX gene candidates in HL patient samples supported the cell line data. Chromosomal analyses demonstrated an amplification of the FOXC1 locus at 6p25 and a gain of the FOXR2 locus at Xp11, indicting genomic aberrations for their upregulation. Comparative expression profiling and ensuing stimulation experiments revealed implementation of the TGFβ- and WNT-signaling pathways in deregulation of FOXD1 and FOXN3. Functional analysis of FOXP1 implicated miR9 and miR34a as upstream regulators and PAX5, TCF3, and RAG2 as downstream targets. A similar exercise for FOXC1 revealed repression of MSX1 and activation of IPO7, both mediating inhibition of the B-cell specific homeobox gene ZHX2. Taken together, our data show that aberrantly expressed FOX genes and their downstream targets are involved in the pathogenesis of HL via deregulation of B-cell differentiation and may represent useful diagnostic markers and/or therapeutic targets.

Sayad A, Akbari MT, Mehdizadeh M, et al.
The association of HLA-class I and class II with Hodgkin's lymphoma in Iranian patients.
Biomed Res Int. 2014; 2014:231236 [PubMed] Free Access to Full Article Related Publications
The Hodgkin's lymphoma disease (HD) is a common malignant neoplasm with germinal centre B-cell origin. It has been suggested that the HLA class I and class II regions have susceptibility effects on HD. In different ethnic groups, different HLA class I and class II alleles affect HD. As a result, there is no consensus which of the different HLA alleles confers susceptibility to HD. In this study, we aimed to ascertain the role of HLA class I and class II alleles in association with Hodgkin's lymphoma in Iranian patients. We performed a case-control genotyping study in 85 Iranian HD patients which were selected from the Bone Marrow Transplantation Department of Taleghani Hospital and 150 controls using the SSP-PCR. Our results demonstrated that the HLA-A*68, HLA-B*51, and HLA-DRB1*15 alleles were significantly more frequent in HD patients in comparison to controls (P = 0.026; OR = 6.188, P = 0.00008; OR = 2.86, P = 0.00006; OR = 5.315, resp.) and they have significant susceptibility effects on HD in Iranian population. There are reports of other populations with regard to consistency and inconsistency to our results. Further studies with large sample size or the meta-analysis are needed to explain the exact associations of HLA gene with HD.

Hosnijeh FS, Lan Q, Rothman N, et al.
Mitochondrial DNA copy number and future risk of B-cell lymphoma in a nested case-control study in the prospective EPIC cohort.
Blood. 2014; 124(4):530-5 [PubMed] Free Access to Full Article Related Publications
It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n = 102) with increasing mtDNA copy number (odds ratio = 1.34, 1.44, and 1.80 for quartiles 2-4, respectively; P trend = .001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis.

Bakhirev AG, Vasef MA, Zhang QY, et al.
Fluorescence immunophenotyping and interphase cytogenetics (FICTION) detects BCL6 abnormalities, including gene amplification, in most cases of nodular lymphocyte-predominant Hodgkin lymphoma.
Arch Pathol Lab Med. 2014; 138(4):538-42 [PubMed] Related Publications
CONTEXT: BCL6 translocations are a frequent finding in B-cell lymphomas of diverse subtypes, including some cases of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). However, reliable analysis of BCL6 rearrangements using fluorescence in situ hybridization is difficult in NLPHL because of the relative paucity of neoplastic cells. Combined immunofluorescence microscopy and fluorescence in situ hybridization, or fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms (FICTION), permits targeted analysis of neoplastic cells.
OBJECTIVE: To better define the spectrum of BCL6 abnormalities in NLPHL using FICTION analysis.
DESIGN: We performed an optimized FICTION analysis of 24 lymph nodes, including 11 NLPHL, 5 follicular hyperplasia with prominent progressive transformation of germinal centers, and 8 follicular hyperplasia without progressive transformation of germinal centers.
RESULTS: BCL6 rearrangement was identified in 5 of 11 cases of NLPHL (46%). In addition, BCL6 gene amplification, with large clusters of BCL6 signals in the absence of chromosome 3 aneuploidy, was detected in 3 of 11 cases of NLPHL (27%). One NLPHL showed extra copies of BCL6 present in conjunction with multiple copies of chromosome 3. Altogether, we detected BCL6 abnormalities in 9 of 11 cases of NLPHL (82%). None of the progressive transformation of germinal centers or follicular hyperplasia cases showed BCL6 abnormalities by FICTION.
CONCLUSIONS: To our knowledge, this is the first report of BCL6 gene amplification in NLPHL. Our optimized protocol for FICTION permits detection of cytogenetic abnormalities in most NLPHL cases and may represent a useful ancillary diagnostic technique.

Koh YW, Park C, Yoon DH, et al.
CSF-1R expression in tumor-associated macrophages is associated with worse prognosis in classical Hodgkin lymphoma.
Am J Clin Pathol. 2014; 141(4):573-83 [PubMed] Related Publications
OBJECTIVES: The aim of this study was to determine the prognostic relevance of colony-stimulating 1 receptor (CSF-1R) expression in both Hodgkin/Reed-Sternberg (HRS) cells and the surrounding cells (non-HRS cells) in patients with classical Hodgkin lymphoma (CHL) .
METHODS: Diagnostic tissues from 112 patients with CHL treated with doxorubicin, bleomycin, vinblastine, and dacarbazine were evaluated retrospectively by immunohistochemical analysis for CSF-1R and CD68 and CD163 for tissue-associated macrophages.
RESULTS: High numbers (≥30%) of non-HRS cells expressing CSF-1R conferred inferior event-free survival and overall survival in univariate and multivariate analysis. High numbers of non-HRS cells expressing CSF-1R were significantly associated with a high number of tumor-associated macrophages as detected by CD163 expression (P < .001). In particular, coexpression of CSF-1R and CD163 was associated with a worse survival outcome than either CSF-1R or CD163 expression alone or no expression.
CONCLUSIONS: Our data demonstrate that a high number of non-HRS cells expressing CSF-1R are correlated with an increased tumor macrophage content and worse survival.

Gunawardana J, Chan FC, Telenius A, et al.
Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma.
Nat Genet. 2014; 46(4):329-35 [PubMed] Related Publications
Classical Hodgkin lymphoma and primary mediastinal B cell lymphoma (PMBCL) are related lymphomas sharing pathological, molecular and clinical characteristics. Here we discovered by whole-genome and whole-transcriptome sequencing recurrent somatic coding-sequence mutations in the PTPN1 gene. Mutations were found in 6 of 30 (20%) Hodgkin lymphoma cases, in 6 of 9 (67%) Hodgkin lymphoma-derived cell lines, in 17 of 77 (22%) PMBCL cases and in 1 of 3 (33%) PMBCL-derived cell lines, consisting of nonsense, missense and frameshift mutations. We demonstrate that PTPN1 mutations lead to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Moreover, silencing of PTPN1 by RNA interference in Hodgkin lymphoma cell line KM-H2 resulted in hyperphosphorylation and overexpression of downstream oncogenic targets. Our data establish PTPN1 mutations as new drivers in lymphomagenesis.

Koh YW, Park CS, Yoon DH, et al.
CD163 expression was associated with angiogenesis and shortened survival in patients with uniformly treated classical Hodgkin lymphoma.
PLoS One. 2014; 9(1):e87066 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent studies have reported the prognostic value of tissue-associated magrophages (TAMs) in classical Hodgkin lymphoma (cHL). In addition, TAMs are implicated in the tumor angiogenesis. In this study, we examined the prognostic relevance of TAMs in relation to vascular endothelial growth factor (VEGF) expression and angiogenesis in uniformly treated cases of cHL.
METHODS: Diagnostic tissue from 116 patients with ABVD-treated cHL was evaluated retrospectively by immunohistochemical analysis for CD68, CD163 and VEGF expression and for CD31 expression as a measure of microvessel density (MVD).
RESULTS: High CD163 expression (≥ 35% of cellularity) correlated with VEGF expression (Pearson's Chi-square test, P = 0.008) and MVD (Spearman correlation coefficient 0.310, P<0.001). High CD163 expression was associated with inferior event-free survival (EFS, P = 0.005) and overall survival (OS, P<0.001) in univariate analysis. In multivariate analysis, high CD163 expression was strongly associated with inferior EFS (P = 0.043) and OS (P = 0.008). Patients with high MVD had a lower OS than those with low MVD, but the difference was not significant (P = 0.071, respectively). While high expression of CD68 was also associated with inferior EFS (P = 0.007), it showed no correlation with VEGF or MVD.
CONCLUSIONS: Our data confirms that CD163 expression provides independent prognostic information in cHL. The correlation of CD163 with VEGF expression and MVD suggests the role of CD163-positive cells in tumor angiogenesis of cHL.

Shay JW
Are short telomeres hallmarks of cancer recurrence?
Clin Cancer Res. 2014; 20(4):779-81 [PubMed] Free Access to Full Article Related Publications
Exposure to radiation and some chemotherapeutic agents is associated with an increased risk of developing second cancers. Short telomeres are almost universally associated with malignant cancer progression. An unanswered question is whether inherited short telomeres or therapy-related telomere shortening is a biomarker of the development of second malignant neoplasms.

Carbone A, Gloghini A
Activated DDR1 increases RS cell survival.
Blood. 2013; 122(26):4152-4 [PubMed] Related Publications
In this issue of Blood, Cader et al show that tumor microenvironment promotes Epstein-Barr virus (EBV)-driven lymphomagenesis in Hodgkin lymphoma by a novel pathway involving latent membrane protein 1 (LMP1) and discoidin domain receptor 1 (DDR1), which is activated by collagen(s) and contributes to the survival of Reed-Sternberg (RS) cells.

Benz AH, Renné C, Maronde E, et al.
Expression and functional relevance of cannabinoid receptor 1 in Hodgkin lymphoma.
PLoS One. 2013; 8(12):e81675 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cannabinoid receptor 1 (CB1) is expressed in certain types of malignancies. An analysis of CB1 expression and function in Hodgkin lymphoma (HL), one of the most frequent lymphomas, was not performed to date.
DESIGN AND METHODS: We examined the distribution of CB1 protein in primary cases of HL. Using lymphoma derived cell lines, the role of CB1 signaling on cell survival was investigated.
RESULTS: A predominant expression of CB1 was found in Hodgkin-Reed-Sternberg cells in a vast majority of classical HL cases. The HL cell lines L428, L540 and KM-H2 showed strong CB1-abundance and displayed a dose-dependent decline of viability under CB1 inhibition with AM251. Further, application of AM251 led to decrease of constitutively active NFκB/p65, a crucial survival factor of HRS-cells, and was followed by elevation of apoptotic markers in HL cells.
CONCLUSIONS: The present study identifies CB1 as a feature of HL, which might serve as a potential selective target in the treatment of Hodgkin lymphoma.

King RL, Howard MT, Bagg A
Hodgkin lymphoma: pathology, pathogenesis, and a plethora of potential prognostic predictors.
Adv Anat Pathol. 2014; 21(1):12-25 [PubMed] Related Publications
Hodgkin lymphoma (HL) encompasses 2 unique clinicopathologic entities, classical Hodgkin lymphoma (CHL) (∼95% of cases) and nodular lymphocyte predominant HL (∼5% of cases). Both subtypes demonstrate a paucity of surreptitious (in CHL) neoplastic B cells within a background of reactive inflammatory cells underscoring both the relatedness of these 2 entities to each other, as well as their distinction from other types of lymphoid neoplasia. Clinically, they are primarily nodal diseases that disseminate in a predictable manner to contiguous nodal regions. The biology of HL as a whole, as well as the genetic and pathologic features that distinguish CHL from nodular lymphocyte predominant HL and other lymphomas has been the subject of a wealth of investigation in recent decades. The aim of this review is to detail the pathologic features of HL and to highlight the recent insights into its molecular basis and the myriad prognostic markers being described.

Gramatges MM, Liu Q, Yasui Y, et al.
Telomere content and risk of second malignant neoplasm in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.
Clin Cancer Res. 2014; 20(4):904-11 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine whether less telomere content was associated with treatment-related second malignant neoplasms (SMN) in childhood cancer survivors.
EXPERIMENTAL DESIGN: Using a nested case-control design, 147 cancer survivors with breast cancer, thyroid cancer, or sarcoma developing after treatment for childhood cancer (cases) were matched (1:1) with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at the time of sample collection, years of follow-up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content as a continuous variable to estimate ORs with corresponding 95% confidence intervals (CI) for development of SMN. ORs were also estimated for specific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma.
RESULTS: There was an inverse relationship between telomere content and SMN, with an adjusted OR of 0.3 per unit change in telomere length to single-copy gene ratio (95% CI, 0.09-1.02; P = 0.05). Patients with thyroid cancer SMN were less likely to have more telomere content (OR, 0.04; 95% CI, 0.00-0.55; P = 0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma.
CONCLUSIONS: A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors.

Frampton M, da Silva Filho MI, Broderick P, et al.
Variation at 3p24.1 and 6q23.3 influences the risk of Hodgkin's lymphoma.
Nat Commun. 2013; 4:2549 [PubMed] Related Publications
In addition to HLA, recent genome-wide association studies (GWASs) of Hodgkin's lymphoma (HL) have identified susceptibility loci for HL at 2p16.1, 8q24.21 and 10p14. In this study, we perform a GWAS meta-analysis with published GWAS (totalling 1,465 cases and 6,417 controls of European background), and follow-up the most significant association signals in 2,024 cases and 1,853 controls. A combined analysis identifies new HL susceptibility loci mapping to 3p24.1 (rs3806624; P=1.14 × 10(-12), odds ratio (OR)=1.26) and 6q23.3 (rs7745098; P=3.42 × 10(-9), OR=1.21). rs3806624 localizes 5' to the EOMES (eomesodermin) gene within a p53 response element affecting p53 binding. rs7745098 maps intergenic to HBS1L and MYB, a region previously associated with haematopoiesis. These findings provide further insight into the genetic and biological basis of inherited susceptibility to HL.

Zhu M, Xu Z, Wang K, et al.
MicroRNA and gene networks in human Hodgkin's lymphoma.
Mol Med Rep. 2013; 8(6):1747-54 [PubMed] Related Publications
There has been significant progress in gene and microRNA (miRNA) research with regard to the morbidity of Hodgkin's lymphoma (HL). However, the regulatory mechanisms of genes and miRNAs have yet to be determined. In the current study, the regulatory association between genes, miRNAs and transcription factors (TFs) was investigated to gain an understanding of the mechanisms and key pathways of HL. The association between TFs and miRNAs, miRNAs and target genes and miRNA and its host gene was examined. To show the regulatory correlation clearly, three regulatory networks were hierarchically constructed: Differentially expressed, associated and global networks. Following comparison and analysis of the similarities and differences among the three networks, a number of key pathways, which showed self-adaptation associations were identified. This included NFκB1 and hsa-miR-9, hsa-miR-196a-1 and its host gene HOXB7, which separately forms a self-adaptation association. The differentially expressed network illuminated the pathogenesis of HL. In addition, the associated network further described the regulatory mechanism associated with HL, including prevention, diagnosis, development and therapy. The current study systematically explains the regulatory mechanisms of HL and supplies comprehensive data associated with HL for further studies. With increasing knowledge of the occurrence, mechanism, improvement, metastasis and treatment, an increased understanding of HL may be achieved.

Cader FZ, Vockerodt M, Bose S, et al.
The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1.
Blood. 2013; 122(26):4237-45 [PubMed] Related Publications
The malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin lymphoma are surrounded by a tumor microenvironment that is composed of a variety of cell types, as well as noncellular components such as collagen. Although HRS cells harbor oncogenic Epstein-Barr virus (EBV) in approximately 50% of cases, it is not known if the tumor microenvironment contributes to EBV-driven lymphomagenesis. We show that expression of the EBV-encoded latent membrane protein-1 (LMP1) in primary human germinal center B cells, the presumed progenitors of HRS cells, upregulates discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen. We also show that HRS cells intimately associated with collagen frequently overexpress DDR1 and that short-term exposure to collagen is sufficient to activate DDR1 in Hodgkin lymphoma-derived cell lines. The ectopic expression of DDR1 significantly increased the survival of collagen-treated DG75 Burkitt lymphoma cells, following etoposide treatment. Conversely, knockdown of DDR1 significantly decreased the survival of collagen-treated L428 Hodgkin lymphoma cells in the absence of specific apoptotic stimulus, suggesting that DDR1 also influences baseline survival. Our results identify a hitherto unknown function for collagen in protecting Hodgkin lymphoma cells from apoptosis and suggest an important contribution of the tumor microenvironment in promoting the oncogenic effects of EBV.

Torres-Espíndola LM, Velázquez-Cruz R, Falfán-Valencia R, et al.
Genetic polymorphism of tumor necrosis factor promoter region and susceptibility to develop Hodgkin lymphoma in a Mexican population.
Leuk Lymphoma. 2014; 55(6):1295-9 [PubMed] Related Publications
Hodgkin lymphoma (HL) is a rare neoplasm of the lymphatic system, in which inflammation and allelic variants in cytokines have been proposed as etiological factors. Epstein-Barr virus infection is often associated as a risk factor in HL and since cytokines are involved in the humoral response to viral infection. Our aim was to study the association between single nucleotide polymorphisms (SNPs) located in the tumor necrosis factor (TNF) gene (- 376G> A, - 238G> A and 581G> A) in a sample of Mexican patients (56 cases) and their susceptibility to develop HL, comparing these SNPs among healthy individuals (127 controls). Frequencies for TNF - 238G> A and TNF 581G> A showed no significant differences between cases and controls. However, the proportion of cases with the GA genotype of - 376 SNP showed a significant difference as compared to controls, odds ratio = 4.41 (95% confidence interval: 1.21-16.6), p = 0.02. We found that in this group of patients from Mexico the SNP - 376G> A in TNF shows an association with higher risk for HL.

Ghesquières H, Maurer MJ, Casasnovas O, et al.
Cytokine gene polymorphisms and progression-free survival in classical Hodgkin lymphoma by EBV status: results from two independent cohorts.
Cytokine. 2013; 64(2):523-31 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cytokines are important immune mediators of classical Hodgkin lymphoma (CHL) pathogenesis, and circulating levels at diagnosis may help predict prognosis. Germline single nucleotide polymorphisms (SNPs) in immune genes have been correlated with cytokine production and function.
METHODS: We investigated whether selected germline SNPs in IL10 (rs1800890, rs1800896, rs1800871, rs1800872), TNFA (rs1800629), IL6 (rs1800795), ILRN (rs419598), INFG (rs2430561) and CCL17 (rs223828) were associated with circulating levels of related cytokines at diagnosis and progression-free survival (PFS) in CHL. Patients were from France (GELA, N=464; median age=32years) and the United States (Iowa/Mayo Specialized Program Of Research Excellence [SPORE], N=239; median age=38years); 22% of 346 CHL cases with EBV tumor status were positive.
RESULTS: There was no association with any of the SNPs with cytokine levels. Overall, there was no association of any of the SNPs with PFS. In exploratory analyses by EBV status, TNFA rs1800629 (HRAA/AG=2.41; 95%CI, 1.17-4.94) was associated with PFS in EBV-negative GELA patients, with similar trends in the SPORE patients (HRAA/AG=1.63; 95%CI, 0.61-4.40). In a meta-analysis of the two studies, TNFA (HRAA/AG=2.11; 95%CI, 1.18-3.77; P=0.01) was statistically significant, and further adjustment for the international prognostic system did not alter this result.
CONCLUSIONS: This study showed that germline variation in TNFA was associated with CHL prognosis for EBV-negative patients, which will require confirmation. These results support broader studies on the differential impact of genetic variation in immune genes on EBV-positive vs. EBV-negative CHL pathogenesis.

Sajesh BV, Lichtensztejn Z, McManus KJ
Sister chromatid cohesion defects are associated with chromosome instability in Hodgkin lymphoma cells.
BMC Cancer. 2013; 13:391 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chromosome instability manifests as an abnormal chromosome complement and is a pathogenic event in cancer. Although a correlation between abnormal chromosome numbers and cancer exist, the underlying mechanisms that cause chromosome instability are poorly understood. Recent data suggests that aberrant sister chromatid cohesion causes chromosome instability and thus contributes to the development of cancer. Cohesion normally functions by tethering nascently synthesized chromatids together to prevent premature segregation and thus chromosome instability. Although the prevalence of aberrant cohesion has been reported for some solid tumors, its prevalence within liquid tumors is unknown. Consequently, the current study was undertaken to evaluate aberrant cohesion within Hodgkin lymphoma, a lymphoid malignancy that frequently exhibits chromosome instability.
METHODS: Using established cytogenetic techniques, the prevalence of chromosome instability and aberrant cohesion was examined within mitotic spreads generated from five commonly employed Hodgkin lymphoma cell lines (L-1236, KM-H2, L-428, L-540 and HDLM-2) and a lymphocyte control. Indirect immunofluorescence and Western blot analyses were performed to evaluate the localization and expression of six critical proteins involved in the regulation of sister chromatid cohesion.
RESULTS: We first confirmed that all five Hodgkin lymphoma cell lines exhibited chromosome instability relative to the lymphocyte control. We then determined that each Hodgkin lymphoma cell line exhibited cohesion defects that were subsequently classified into mild, moderate or severe categories. Surprisingly, ~50% of the mitotic spreads generated from L-540 and HDLM-2 harbored cohesion defects. To gain mechanistic insight into the underlying cause of the aberrant cohesion we examined the localization and expression of six critical proteins involved in cohesion. Although all proteins produced the expected nuclear localization pattern, striking differences in RAD21 expression was observed: RAD21 expression was lowest in L-540 and highest within HDLM-2.
CONCLUSION: We conclude that aberrant cohesion is a common feature of all five Hodgkin lymphoma cell lines evaluated. We further conclude that aberrant RAD21 expression is a strong candidate to underlie aberrant cohesion, chromosome instability and contribute to the development of the disease. Our findings support a growing body of evidence suggesting that cohesion defects and aberrant RAD21 expression are pathogenic events that contribute to tumor development.

Sánchez-Espiridión B, Martín-Moreno AM, Montalbán C, et al.
MicroRNA signatures and treatment response in patients with advanced classical Hodgkin lymphoma.
Br J Haematol. 2013; 162(3):336-47 [PubMed] Related Publications
Although specific microRNA (miRNA) signatures in classical Hodgkin lymphoma (cHL) have been proposed, their relationship with clinical outcome remains unclear. Despite treatment advances, a substantial subset of patients with advanced cHL are refractory to standard therapies based on adriamycin and its variants. Global miRNA expression data of 29 advanced cHL patients and five cHL-derived cell lines were used to identify profiles from Hodgkin-Reed-Sternberg (HRS) cells and their non-tumoural microenvironment. A cHL-miRNA signature was identified with 234 miRNAs differentially expressed. A subset of these miRNAs was associated with outcome and selected for study in an independent set of 168 cHL samples using quantitative reverse transcription polymerase chain reaction. Multivariate Cox regression analyses including cross-validation with failure-free survival (FFS) as clinical endpoint revealed a miRNA signature with MIR21, MIR30E, MIR30D and MIR92B* that identified two risk-groups with significant differences in 5-year FFS (81% vs. 35.7%; P < 0.001). Additionally, functional silencing of MIR21 and MIR30D in L428 cells showed increased sensitivity to doxorubicin-induced apoptosis, pointing towards abnormalities of mitochondrial intrinsic and TP53-CDKN1A pathways as related to miRNA deregulation in cHL. These results suggest that clinical outcome in cHL is associated with a specific miRNA signature. Moreover, functional analyses suggest a role for MIR21 and MIR30D in cHL pathogenesis and therapeutic resistance.

Navarro A, Muñoz C, Gaya A, et al.
MiR-SNPs as markers of toxicity and clinical outcome in Hodgkin lymphoma patients.
PLoS One. 2013; 8(5):e64716 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In recent years, microRNA (miRNA) pathways have emerged as a crucial system for the regulation of tumorogenesis. miR-SNPs are a novel class of single nucleotide polymorphisms that can affect miRNA pathways.
DESIGN AND METHODS: We analyzed eight miR-SNPs by allelic discrimination in 141 patients with Hodgkin lymphoma and correlated the results with treatment-related toxicity, response, disease-free survival (DFS) and overall survival (OS).
RESULTS: The KRT81 (rs3660) GG genotype was associated with an increased risk of neurological toxicity (P = 0.016), while patients with XPO5 (rs11077) AA or CC genotypes had a higher rate of bleomycin-associated pulmonary toxicity (P = 0.048). Both miR-SNPs emerged as independent factors in the multivariate analysis. The XPO5 AA and CC genotypes were also associated with a lower response rate (P = 0.036). XPO5 (P = 0.039) and TRBP (rs784567) (P = 0.022) genotypes emerged as prognostic markers for DFS, and XPO5 was also associated with OS (P = 0.033). In the multivariate analysis, only XPO5 emerged as an independent prognostic factor for DFS (HR: 2.622; 95%CI 1.039-6.620; P = 0.041). Given the influence of XPO5 and TRBP as individual markers, we then investigated the combined effect of these miR-SNPs. Patients with both the XPO5 AA/CC and TRBP TT/TC genotypes had the shortest DFS (P = 0.008) and OS (P = 0.008).
CONCLUSION: miR-SNPs can add useful prognostic information on treatment-related toxicity and clinical outcome in Hodgkin lymphoma and can be used to identify patients likely to be chemoresistant or to relapse.

Hartmann S, Tousseyn T, Döring C, et al.
Macrophages in T cell/histiocyte rich large B cell lymphoma strongly express metal-binding proteins and show a bi-activated phenotype.
Int J Cancer. 2013; 133(11):2609-18 [PubMed] Related Publications
Abundant macrophage infiltration in tumors often correlates with a poor prognosis. T cell/histiocyte rich large B cell lymphoma (THRLBCL) is a distinct aggressive B cell lymphoma entity showing a high macrophage content. To further elucidate the role of tumor-associated macrophages in THRLBCL, we performed gene expression profiling of microdissected histiocyte subsets of THRLBCL, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), Piringer lymphadenitis, sarcoidosis, nonspecific lymphadenitis and monocytes from peripheral blood. In a supervised principal component analysis, histiocytes from THRLBCL were most closely related to epithelioid cells from NLPHL, with both types of cells expressing genes related to proinflammatory and regulatory macrophage activity. Moreover, histiocytes from THRLBCL strongly expressed metal-binding proteins like MT2A, by which histiocytes of THRLBCL can be distinguished from the other histiocyte subsets investigated. Interestingly, the validation at the protein level showed a strong expression of TXN, CXCL9, MT2A and SOD2 not only in macrophages of THRLBCL but also in the tumor cells of NLPHL and classical Hodgkin lymphoma (cHL). Overall, the present findings indicate that macrophages in the microenvironment of THRLBCL have acquired a distinct gene expression pattern that is characterized by a mixed M1/M2 phenotype and a strong expression of several metal binding proteins. The microenvironments in NLPHL and THRLBCL appear to have a similar influence on the macrophage phenotype. The high expression of metal binding proteins in histiocytes of THRLBCL may be diagnostically useful, but a potential pathophysiological role remains to be identified.

Cen J, Shen J, Wang X, et al.
Association between lymphoma prognosis and aberrant methylation of ID4 and ZO-1 in bone marrow and paraffin-embedded lymphoma tissues of treatment-naive patients.
Oncol Rep. 2013; 30(1):455-61 [PubMed] Related Publications
The aim of the present study was to investigate the association between lymphoma prognosis and aberrant methylation of inhibitor of DNA binding factor 4 (ID4) and tight junction protein 1 (ZO-1) genes in samples isolated from the bone marrow and paraffin-embedded lymphoma tissues of treatment-naive lymphoma patients. The bone marrow biopsy and paraffin-embedded lymphoma tissue samples from treatment-naive lymphoma patients were obtained, along with corresponding control samples from subjects without lymphoma and from lymph nodes of chronic cholecystitis and reactive lymphadenitis patients. Methylation-specific PCR (MSP) reactions were performed to analyze the methylation status on the promoter regions of ID4 and ZO-1. ID4 and ZO-1 promoter regions in the control group were completely unmethylated, whereas the rates of methylation of ID4 and ZO-1 in paraffin-embedded lymphoma tissues of the lymphoma patients were 80.4 and 84.3%, respectively. The methylation positivity rates of both the ID4 or ZO-1 genes in lymphoma patients were 92.2%, which was significantly higher compared to the rates in the control group (0%). The methylation positivity rates of the ID4 and ZO-1 genes in the bone marrow and paraffin-embedded lymphoma tissues of non-Hodgkin lymphoma patients were significantly higher compared to the rates in the Hodgkin lymphoma patients. The survival rate of lymphoma patients with methylated ID4 was significantly lower compared to that of patients with unmethylated ID4. The methylation of the ID4 and ZO-1 genes may be a specific molecular marker for lymphoma diagnosis. The methylation of the ID4 gene may be an indicator of poor prognosis in lymphoma patients.

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