Hodgkin Lymphoma - Molecular Biology


Literature Analysis

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

  • CDKN2A
  • Alleles
  • DNA Methylation
  • NF-kappa B
  • Protein Kinases
  • World Health Organization
  • DNA-Binding Proteins
  • Staging
  • Chromosome Aberrations
  • Cancer Gene Expression Regulation
  • Mutation
  • Genetic Predisposition
  • Herpesvirus 4, Human
  • Immunohistochemistry
  • B-Cell Lymphoma
  • Disease-Free Survival
  • Childhood Cancer
  • Lymphocytes
  • Diffuse Large B-Cell Lymphoma
  • FISH
  • Epstein-Barr Virus Infections
  • Apoptosis
  • Reed-Sternberg Cells
  • Cancer DNA
  • BCL11A
  • SH2D1A protein, human
  • Oncogene Proteins
  • Hodgkin Lymphoma
  • DNA Mutational Analysis
  • Genotype
  • Base Sequence
  • Oligonucleotide Array Sequence Analysis
  • Adolescents
  • inosine monophosphate synthase
  • MicroRNAs
  • Polymerase Chain Reaction
  • Biomarkers, Tumor
  • CD Antigens
  • Case-Control Studies
  • B-Lymphocytes
  • Pedigree
  • Nuclear Proteins
  • BCL3
  • Gene Expression Profiling
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (32)

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'.

REL 2p13-p12 C-Rel -REL and Hodgkin Lymphoma
CD68 17p13.1 GP110, LAMP4, SCARD1 -CD68 and Hodgkin Lymphoma
CDKN2A 9p21.3 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
NFKBIA 14q13.2 IKBA, MAD-3, NFKBI -NFKBIA and Hodgkin Lymphoma
CD79A 19q13.2 IGA, MB-1 -CD79A and Hodgkin Lymphoma
IL13 5q31.1 P600, IL-13 -IL13 and Hodgkin Lymphoma
STAT6 12q13.3 STAT6B, STAT6C, D12S1644, IL-4-STAT -STAT6 and Hodgkin Lymphoma
HLA-DPB1 6p21.32 DPB1, HLA-DP, HLA-DPB, HLA-DP1B -HLA-DPB1 and Hodgkin Lymphoma
IRF4 6p25.3 MUM1, LSIRF, SHEP8, NF-EM5 -IRF4 and Hodgkin Lymphoma
TNFAIP3 6q23.3 A20, AISBL, OTUD7C, TNFA1P2 -TNFAIP3 and Hodgkin Lymphoma
CD79B 17q23.3 B29, IGB, AGM6 -CD79B and Hodgkin Lymphoma
CD274 9p24.1 B7-H, B7H1, PDL1, PD-L1, PDCD1L1, PDCD1LG1 -CD274 and Hodgkin Lymphoma
BCL11A 2p16.1 EVI9, CTIP1, ZNF856, HBFQTL5, BCL11A-L, BCL11A-S, BCL11a-M, BCL11A-XL -BCL11A and Hodgkin Lymphoma
BCL3 19q13.32 BCL4, D19S37 -BCL3 and Hodgkin Lymphoma
CCL17 16q21 TARC, ABCD-2, SCYA17, A-152E5.3 -CCL17 and Hodgkin Lymphoma
POU2AF1 11q23.1 BOB1, OBF1, OCAB, OBF-1 -POU2AF1 and Hodgkin Lymphoma
TIA1 2p13 WDM, TIA-1 -TIA1 and Hodgkin Lymphoma
PTPN1 20q13.13 PTP1B -PTPN1 mutations in Hodgkin Lymphoma and PMBCL
CCL22 16q21 MDC, ABCD-1, SCYA22, STCP-1, DC/B-CK, A-152E5.1 -CCL22 and Hodgkin Lymphoma
TRAF3 14q32.32 CAP1, LAP1, CAP-1, CRAF1, IIAE5, CD40bp -TRAF3 and Hodgkin Lymphoma
CD163 12p13.3 M130, MM130 -CD163 and Hodgkin Lymphoma
PDCD1LG2 9p24.1 B7DC, Btdc, PDL2, CD273, PD-L2, PDCD1L2, bA574F11.2 -PDCD1LG2 and Hodgkin Lymphoma
POU2F2 19q13.2 OCT2, OTF2, Oct-2 -POU2F2 and Hodgkin Lymphoma
IL13RA1 Xq24 NR4, CT19, CD213A1, IL-13Ra -IL13RA1 and Hodgkin Lymphoma
ATIC 2q35 PURH, AICAR, AICARFT, IMPCHASE, HEL-S-70p -ATIC and Hodgkin Lymphoma
TBX21 17q21.32 TBET, T-PET, T-bet, TBLYM -TBX21 and Hodgkin Lymphoma
FUT4 11q21 LeX, CD15, ELFT, FCT3A, FUTIV, SSEA-1, FUC-TIV -FUT4 and Hodgkin Lymphoma
DDR2 1q23.3 TKT, WRCN, MIG20a, NTRKR3, TYRO10 -DDR2 and Hodgkin Lymphoma
SH2D1A Xq25 LYP, SAP, XLP, DSHP, EBVS, IMD5, XLPD, MTCP1, XLPD1, SAP/SH2D1A -SH2D1A and Hodgkin Lymphoma
PRF1 10q22.1 P1, PFP, FLH2, PFN1, HPLH2 -PRF1 and Hodgkin Lymphoma
IL4R 16p12.1 CD124, IL4RA, IL-4RA -IL4R and Hodgkin Lymphoma
TNFRSF8 1p36.22 CD30, Ki-1, D1S166E -TNFRSF8 and Hodgkin Lymphoma

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

Latest Publications

Millett R, Aggarwal A, Tabbara I, Nassereddine S
Chronic Myeloid Leukemia as Secondary Malignancy Following the Treatment of Hodgkin Lymphoma: A Case Series.
Anticancer Res. 2019; 39(8):4333-4335 [PubMed] Related Publications
Secondary malignancies are relatively common and clinically important phenomena following both chemotherapy and radiotherapy. The majority of these cases are acute leukemias, the occurrence of which have been thoroughly documented and studied. More rarely, chronic myeloid leukemias (CML) may arise subsequent to treatment of a primary malignancy. Literature review on such developments following treatment of Hodgkin's Lymphoma (HL) is scant. Herein, the authors present three cases of CML diagnosed within five years of treatment initiation for Hodgkin's Lymphoma (HL); one of the three patients had CML with atypical variant carrying a rare mutation with BCR-JAK2 fusion.

Silva OB, Correia NAA, de Barros FT, et al.
3' untranslated region A>C (rs3212227) polymorphism of Interleukin 12B gene as a potential risk factor for Hodgkin's lymphoma in Brazilian children and adolescents.
Tumour Biol. 2019; 41(7):1010428319860400 [PubMed] Related Publications
Interleukin 12 plays an important role in immunoregulation between the T helper 1/T helper 2 lymphocytes and in the antiviral and antitumor immune response. The aim of this study was to investigate the possible association between the interleukin 12B polymorphism rs3212227 and the risk to develop Hodgkin's lymphoma in childhood and adolescents. A total of 100 patients with Hodgkin's lymphoma and a group of 181 healthy controls were selected at random from a forensic laboratory of the University of Pernambuco. The AA genotype was detected in the controls (53.04%) and the AC genotype was found in the patients (54%). The AC genotype showed an association with the development of Hodgkin's lymphoma (odds ratio = 2.091, 95% confidence interval = 1.240-3.523, p = 0.007). When AC + CC genotypes were analyzed together, an increase in risk of 1.9 times more chances for HL development could be observed (odds ratio = 1.923, 95% confidence interval = 1.166-3.170, p = 0.014). However, there was no association between the AC and CC genotypes of the interleukin 12B polymorphism with the clinical risk group (p = 0.992, p = 0.648, respectively). Our results suggest that the presence of the C allele may be contributing to the development of Hodgkin's lymphoma in children and adolescents.

Kaasinen E, Kuismin O, Rajamäki K, et al.
Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.
Nat Commun. 2019; 10(1):1252 [PubMed] Free Access to Full Article Related Publications
Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.

Genov N, Basti A, Abreu M, Relógio A
Temporal Splicing Switches in Elements of the TNF-Pathway Identified by Computational Analysis of Transcriptome Data for Human Cell Lines.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Alternative splicing plays an important role in numerous cellular processes and aberrant splice decisions are associated with cancer. Although some studies point to a regulation of alternative splicing and its effector mechanisms in a time-dependent manner, the extent and consequences of such a regulation remains poorly understood. In the present work, we investigated the time-dependent production of isoforms in two Hodgkin lymphoma cell lines of different progression stages (HD-MY-Z, stage IIIb and L-1236, stage IV) compared to a B lymphoblastoid cell line (LCL-HO) with a focus on tumour necrosis factor (TNF) pathway-related elements. For this, we used newly generated time-course RNA-sequencing data from the mentioned cell lines and applied a computational pipeline to identify genes with isoform-switching behaviour in time. We analysed the temporal profiles of the identified events and evaluated in detail the potential functional implications of alterations in isoform expression for the selected top-switching genes. Our data indicate that elements within the TNF pathway undergo a time-dependent variation in isoform production with a putative impact on cell migration, proliferation and apoptosis. These include the genes

Küppers R, Schneider M, Hansmann ML
Laser-Based Microdissection of Single Cells from Tissue Sections and PCR Analysis of Rearranged Immunoglobulin Genes from Isolated Normal and Malignant Human B Cells.
Methods Mol Biol. 2019; 1956:61-75 [PubMed] Related Publications
Normal and malignant B cells carry rearranged immunoglobulin (Ig) variable region genes, which due to their practically limitless diversity represent ideal clonal markers for these cells. We describe here an approach to isolate single cells from frozen tissue sections by microdissection using a laser-based method. From the isolated cells, rearranged IgH and Igκ genes are amplified in a semi-nested PCR approach, using a collection of V gene subgroup-specific primers recognizing nearly all V genes together with primers for the J genes. By sequence analysis of V region genes from distinct cells, the clonal relationship of the B lineage cells can unequivocally be determined and related to the histological distribution of the cells. The approach is also useful to determine V, D, and J gene usage. Moreover, the presence and pattern of somatic Ig V gene mutations give valuable insight into the stage of differentiation of the B cells.

Herrera AF
Where does PD-1 blockade fit in HL therapy?
Hematology Am Soc Hematol Educ Program. 2018; 2018(1):213-220 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Genetic alterations of the

Sud A, Thomsen H, Orlando G, et al.
Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma.
Blood. 2018; 132(19):2040-2052 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of 7 genome-wide association studies totaling 5325 HL cases and 22 423 control patients. We identify 5 new HL risk loci at 6p21.31 (rs649775;

Wąsik-Szczepanek E, Szymczyk A, Szczepanek D, et al.
Richter syndrome: A rare complication of chronic lymphocytic leukemia or small lymphocytic lymphoma.
Adv Clin Exp Med. 2018; 27(12):1683-1689 [PubMed] Related Publications
BACKGROUND: Richter's syndrome (RS) is a rare complication with an unfavorable prognosis, in which chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) transform into a more aggressive type of lymphoma, most commonly into diffuse large B cell lymphoma (DLBCL) or less often into Hodgkin's lymphoma (HL).
OBJECTIVES: The objective of this research paper was to present a retrospective analysis of patients with CLL/SLL whose disease transformed into RS.
MATERIAL AND METHODS: The study included 217 patients (100 women and 107 men) with CLL/SLL diagnosed in the years 2006-2015 at the Department of Hematooncology and Bone Marrow Transplantation of the Medical University of Lublin, which transformed into RS. We analyzed clinical, laboratory, immunophenotypic (ZAP-70 and CD38 expression), histopathological, and genetic data (del(17p), del(11q)), which was collected at the time of CLL/SLL diagnosis, and some which was collected at the time of transformation.
RESULTS: Richter's syndrome was diagnosed in 4.6% of all CLL and SLL patients. The group of patients with RS consisted of 9 patients with primary CLL and 1 patient with a diagnosis of SLL (8 patients with transformation into DLBCL and 2 patients with transformation into HL). Leukemic lymphocytes showed evidence of peripheral blood lymphocyte membrane expression of ZAP70+/CD38+ (1 patient), of ZAP-70+/CD38- (3 patients), of ZAP-70-/CD38- (1 patient), and of ZAP-70-/CD38+ (5 patients). The deletion of 11q (del(11q)) was documented in 2 patients. In 4 cases, the location of RS was extremely rare (the thyroid gland, liver, skin, bladder, and central nervous system).
CONCLUSIONS: Richter's syndrome is a rare, but probable complication of CLL/SLL with an unfavorable prognosis, and it should be taken into account at every stage of the disease, particularly when the course of the disease is aggressive.

Pan L, Tang W, Zhang A, et al.
Identification of the novel HLA-A*29:113 allele in a Hodgkin's Lymphoma patient.
HLA. 2018; 92(5):322-323 [PubMed] Related Publications
HLA-A*29:113 allele differs from HLA-A*29:01:01 at position 517 within exon 3.

Vera-Lozada G, Segges P, Stefanoff CG, et al.
Pathway-focused gene expression profiles and immunohistochemistry detection identify contrasting association of caspase 3 (CASP3) expression with prognosis in pediatric classical Hodgkin lymphoma.
Hematol Oncol. 2018; 36(4):663-670 [PubMed] Related Publications
The search for clinically relevant molecular markers in classical Hodgkin lymphoma (cHL) is hampered by the histopathological complexity of the disease, resulting from the admixture of a small number of neoplastic Hodgkin and Reed-Sternberg (H-RS) cells with an abundant and heterogeneous microenvironment. In this study, we evaluated gene expression profiles of 11 selected genes previously proposed as a molecular score for adult cHL, aiming to validate its application in the pediatric setting. Assays were performed by RT-qPCR from formalin-fixed paraffin-embedded (FFPE) lymph nodes in 80 patients with cHL. Selected genes were associated with cell cycle (CENPF, CDK1, CCNA2, CCNE2, and HMMR), apoptosis (BCL2, BCL2L1, and CASP3), and monocytes/macrophages (LYZ and STAT1). Despite using controlled preanalytical and analytical strategies, we were not able to validate the 11-gene score to be applied in pediatric cHL. Principal component analysis (PCA) disclosed 3 components that accounted for 65.7% of the total variability. The second PC included microenvironment and apoptosis genes, from which CASP3 expression was associated with a short time of progression-free survival, which impact was maintained in the unfavorable risk group, Epstein-Barr virus-negative cases, and multivariate analysis (P < .05). Because this is a counterintuitive association, CASP3 active expression was assessed at the protein level in H-RS cells by double immunohistochemistry. In contrast to the association of mRNA levels with a poor therapeutic response, a high number of cleaved CASP3+ cells were associated with longer progression-free survival (P = .03) and overall survival (P = .002). Our results demonstrate the feasibility of using FFPE samples as RNA source for molecular prognostication, but argue against the concept of direct and wide applicability of molecular scores in cHL. We reinforce the potential of CASP3 as an interesting target to be explored in adult and pediatric cHL, and alert for its dual biological role in H-RS cells and tumor microenvironment.

McMaster ML, Sun C, Landi MT, et al.
Germline mutations in Protection of Telomeres 1 in two families with Hodgkin lymphoma.
Br J Haematol. 2018; 181(3):372-377 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
In a previous whole exome sequencing of patients from 41 families with Hodgkin lymphoma, we identified two families with distinct heterozygous rare coding variants in POT1 (D224N and Y36H), both in a highly conserved region of the gene. POT1 D224N mutant did not bind to a single-stranded telomere oligonucleotide in vitro suggesting the mutation perturbs POT1's ability to bind to the telomeric G-rich overhang. Human HT1080 cells expressing POT1 D224N and lymphoblastoid cells carrying Y36H both showed increased telomere length and fragility in comparison to wild type cells. This strongly suggests that mutant POT1 causes chromosome instability and may play a role in lymphomagenesis in these families.

Zhang Y, Tong L, Chen S, et al.
Analysis of NFKB2‑mediated regulation of mechanisms underlying the development of Hodgkin's lymphoma.
Mol Med Rep. 2018; 17(6):8129-8136 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Nuclear factor‑κB (NF‑κB) is widely involved in various lymphoid malignancies. However, its exact functional role and potential regulatory mechanisms in Hodgkin's lymphoma (HL) remains unclear. The present study aimed to investigate the regulatory mechanism of NF‑κB in HL by analysis of a gene expression profile that was obtained from HL cells with or without NF‑κB subunit 2 (NFKB2) knockdown. The GSE64234 dataset containing 6 HL cell line specimens transfected with small interfering (si)RNA against NFKB2 and 6 control specimens transfected with non‑targeting siRNA sequences was downloaded from the Gene Expression Omnibus database. Based on these data, differentially expressed genes (DEGs) were screened for following data preprocessing. Functional enrichment analysis was subsequently conducted among the identified upregulated and downregulated DEGs. Additionally, a protein‑protein interaction (PPI) network was constructed and module analyses were performed. Finally, microRNAs (miRNAs/miRs) targeting the identified DEGs were predicted for the construction of a miRNA‑target regulatory network. A total of 253 DEGs were identified, consisting of 109 upregulated and 144 downregulated DEGs. Pathway enrichment analysis revealed that B‑cell lymphoma 2‑like 1 (BCL2L1) was significantly enriched in the NF‑κB signaling pathway, and colony‑stimulating factor 2 (CSF2) and BCL2L1 were enriched in the Jak‑signal transducer and activator of transcription (STAT) signaling pathway. BCL2L1 and CSF2 were determined to be hub genes in the PPI network. A total of 6 miRNAs, including let‑7a‑5p, miR‑9‑5p, miR‑155‑5p, miR‑135a‑5p, miR‑17‑5p and miR‑375, were identified in the miRNA‑target regulatory network. The results of the present study indicated that NFKB2 may be involved in HL development through regulation of BCL2L1, CSF2, miR‑135a‑5p, miR‑155‑5p and miR‑9‑5p expression, as well as the modulation of Jak‑STAT and NF‑κB signaling pathways.

Tiacci E, Ladewig E, Schiavoni G, et al.
Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma.
Blood. 2018; 131(22):2454-2465 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Dissecting the pathogenesis of classical Hodgkin lymphoma (cHL), a common cancer in young adults, remains challenging because of the rarity of tumor cells in involved tissues (usually <5%). Here, we analyzed the coding genome of cHL by microdissecting tumor and normal cells from 34 patient biopsies for a total of ∼50 000 singly isolated lymphoma cells. We uncovered several recurrently mutated genes, namely,

Spina V, Bruscaggin A, Cuccaro A, et al.
Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma.
Blood. 2018; 131(22):2413-2425 [PubMed] Related Publications
The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep next-generation sequencing approach for circulating tumor DNA (ctDNA), we aimed to identify the genetics of cHL in different clinical phases, as well as its modifications on treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory patients with cHL, including longitudinal samples collected under ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy. ctDNA mirrored Hodgkin and Reed-Sternberg cell genetics, thus establishing ctDNA as an easily accessible source of tumor DNA for cHL genotyping. By identifying

Tanaka Y, Maeshima AM, Nomoto J, et al.
Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma.
Eur J Haematol. 2018; 100(5):511-517 [PubMed] Related Publications
OBJECTIVES: We aimed at investigating the relationship between classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBL), and gray zone lymphoma (GZL) with intermediate characteristics between cHL and PMBL, from the perspective of the aberration in programed cell death 1 and the programed death ligands (PDLs) network.
METHODS: We explored the expression levels of PDLs and chromosomal anomalies in 67 cases: 34 cases with cHL, 20 with PMBL, and 13 with GZL, using immunohistochemical analyses and Fluorescence In Situ Hybridization (FISH).
RESULTS: Twenty-one cHL (62%), 3 PMBL (15%), and 6 GZL (46%) cases showed staining to PD-L1 antibodies in more than 70% of tumor cells. Two cHL (6%), 10 PMBL (50%), and 3 GZL (23%) cases were not stained by PD-L1 antibodies. Patients over 40 years old manifest more frequent expression of PD-L1 in cHL. Proportion of tumors stained by PD-L2 antibody was increased in PMBL. FISH analyses with a PD-L1/PD-L2 probe detected 5 amplification, 1 gain, and 7 polysomy cases in cHL, 1 amplification and 1 polysomy case in GZL, and amplification in 1 PMBL case.
CONCLUSION: We identified increased staining of PD-L1 in cHL and that of PD-L2 in PMBL. GZL had a pattern similar to that of cHL.

Winter S, Martin E, Boutboul D, et al.
Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility.
EMBO Mol Med. 2018; 10(2):188-199 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T-lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein-Barr virus (EBV) infection. RASGRP1 is a T-lymphocyte-specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in

Khodadad K, Karimi S, Esfahani-Monfared Z, et al.
Correlation of Minichromosome Maintenance Protein 6 Expression Rate and Clinical Outcome in Patients With Hodgkin's Lymphoma.
Acta Med Iran. 2017; 55(9):550-555 [PubMed] Related Publications
Minichromosome maintenance complex component 6 (MCM-6) is one of the six proteins of the MCM family, which are involved in the initiation of DNA replication, represents a marker of proliferating cells. The goal of this study was to evaluate the prognostic relevance of the neoplastic cell proliferation rate in patients with Hodgkin's lymphoma (HL). We evaluated the formalin-fixed paraffin-embedded lymph node biopsy specimens from 55 patients by using monoclonal antibody against MCM-6 and compared these findings with clinical data and treatment outcome. Median of MCM-6 expression was 85% (range: 35%-99%). In multivariate analysis, MCM-6 expression, B symptoms, and age were not statistically significant predictor for relapse in contrary to response (P=.001) and stage of disease (P=.048). Patients with lower MCM-6 expression rates showed higher relapse rate and lower disease-free survival (DFS). Meanwhile, patients with MCM-6 expression less than 85% showed shorter DFS (P=.031). We hypothesize that in group of patients with lower MCM-6 expression rate, a larger proportion of proliferating malignant cells are arrested in the very early phase of mitosis, in comparison to the group of patients with higher MCM-6 expression, and this could imply a shorter and probably higher relapse rate in the former group.

Sud A, Thomsen H, Law PJ, et al.
Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility.
Nat Commun. 2017; 8(1):1892 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Several susceptibility loci for classical Hodgkin lymphoma have been reported. However, much of the heritable risk is unknown. Here, we perform a meta-analysis of two existing genome-wide association studies, a new genome-wide association study, and replication totalling 5,314 cases and 16,749 controls. We identify risk loci for all classical Hodgkin lymphoma at 6q22.33 (rs9482849, P = 1.52 × 10

Khare D, Goldschmidt N, Bardugo A, et al.
Plasma microRNA profiling: Exploring better biomarkers for lymphoma surveillance.
PLoS One. 2017; 12(11):e0187722 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
Early detection of relapsed lymphoma improves response and survival. Current tools lack power for detection of early relapse, while being cumbersome and expensive. We searched for sensitive biomarkers that precede clinical relapse, and serve for further studies on therapy response and relapse. We recruited 20 healthy adults, 14 diffuse large B-cell lymphoma (DLBCL) patients and 11 Hodgkin lymphoma (HL) patients at diagnosis. Using small-RNA sequencing we identified in DLBCL patients increased plasma levels of miR-124 and miR-532-5p, and decreased levels of miR-425, miR-141, miR-145, miR-197, miR-345, miR-424, miR-128 and miR-122. In the HL group, we identified miR-25, miR-30a/d, miR-26b, miR-182, miR-186, miR-140* and miR-125a to be up-regulated, while miR-23a, miR-122, miR-93 and miR-144 were down-regulated. Pathway analysis of potential mRNAs targets of these miRNA revealed in the DLBCL group potential up-regulation of STAT3, IL8, p13k/AKT and TGF-B signaling, and potential down-regulation of the PTEN and p53 pathways; while in the HL group we have found the cAMP-mediated pathway and p53 pathway to be potentially down-regulated. Survival analyses revealed that plasma levels of miR-20a/b, miR-93 and miR-106a/b were associated with higher mortality. In conclusion, we identified sets of dysregulated circulating miRNA that might serve as reliable biomarkers for relapsed lymphoma.

Carbone A, Gloghini A
How immunologic and genetic biomarkers impact Hodgkin lymphoma classification, diagnosis, and management: a huge potential that yet needs to be exploited.
Int J Biol Markers. 2018; 33(2):137-140 [PubMed] Related Publications
"Ne è passata di acqua sotto i ponti." It has been a long time since the diagnosis of Hodgkin lymphoma (HL) was exclusively based on the detection of typical Reed-Sternberg cells and the recognition of the characteristic morpho-histological background, as well as on the pathologist's skill. The discovery of immunologic, molecular genetic and virologic biomarkers has provided an objective contribution to the diagnosis and a scientific basis for a modern classification of HL. Recent updates have clarified the nature of the so-called nodular lymphocyte predominant HL and its link to the T-cell/histiocyte-rich large B-cell lymphomas as well as its relationship with the lymphocyte-rich subset of classical HL (CHL). Molecular virology studies assessed a role for the Epstein-Barr virus in the pathogenesis of a fraction of CHL of the general population, and virtually in all cases of CHL occurring in people infected by HIV. Finally, immunologic and genetic findings corroborated the existence of grey zone lymphomas at the edges of CHL. Overall, these advances provided additional and useful information to address the treatment of patients affected by HL.

Faizan M, Kashif RUA, Anwar S, Safdar M
Familial Hodgkin Lymphoma.
J Coll Physicians Surg Pak. 2017; 27(9):572-573 [PubMed] Related Publications
Hodgkin Lymphoma (HL) is a lymphoid tumour that represents about 1% of all neoplasms occurring worldwide. HLis the most treatable of childhood malignancies. The etiology of HLis unknown. However, increase risk has been reported in males, with autoimmune diseases, poor socioeconomic status, increased family size, Ebstein Barr Virus (EBV) exposure, congenital or acquired immunodeficiency and those with a family history of HL. Familial HLis rare. The risk of developing HLis increased six times in the siblings of the affected patients. Both genetic and environmental factors have been postulated in the pathogenesis. No case of familial HLhas been reported in the literature from Pakistan. We report two families with familial HLoccurring in siblings that have been successfully treated and are on our follow-up.

Yamazaki F, Shima H, Osumi T, et al.
Nodular Lymphocyte-predominant Hodgkin Lymphoma in a 15-Year-Old Boy With Li-Fraumeni Syndrome Having a Germline TP53 D49H Mutation.
J Pediatr Hematol Oncol. 2018; 40(3):e195-e197 [PubMed] Related Publications
Germline mutations in TP53 are the primary cause of Li-Fraumeni syndrome (LFS). Most mutations are reported within the DNA-binding domain. We report a case of a 15-year-old boy with LFS who developed early-stage nodular lymphocyte-predominant Hodgkin lymphoma, a rare subtype of Hodgkin lymphomas. His sister was diagnosed with embryonal rhabdomyosarcoma at the age of 1.5 years. Sequence analysis revealed a germline mutation in the transactivation domain of TP53, c.145G>C (p.D49H), in the patient, his sister, and father. One family with LFS with a germline TP53 D49H mutation has previously been reported. This report supports the pathogenicity of this mutation.

Chan FC, Mottok A, Gerrie AS, et al.
Prognostic Model to Predict Post-Autologous Stem-Cell Transplantation Outcomes in Classical Hodgkin Lymphoma.
J Clin Oncol. 2017; 35(32):3722-3733 [PubMed] Related Publications
Purpose Our aim was to capture the biology of classical Hodgkin lymphoma (cHL) at the time of relapse and discover novel and robust biomarkers that predict outcomes after autologous stem-cell transplantation (ASCT). Materials and Methods We performed digital gene expression profiling on a cohort of 245 formalin-fixed, paraffin-embedded tumor specimens from 174 patients with cHL, including 71 with biopsies taken at both primary diagnosis and relapse, to investigate temporal gene expression differences and associations with post-ASCT outcomes. Relapse biopsies from a training cohort of 65 patients were used to build a gene expression-based prognostic model of post-ASCT outcomes (RHL30), and two independent cohorts were used for validation. Results Gene expression profiling revealed that 24% of patients exhibited poorly correlated expression patterns between their biopsies taken at initial diagnosis and relapse, indicating biologic divergence. Comparative analysis of the prognostic power of gene expression measurements in primary versus relapse specimens demonstrated that the biology captured at the time of relapse contained superior properties for post-ASCT outcome prediction. We developed RHL30, using relapse specimens, which identified a subset of high-risk patients with inferior post-ASCT outcomes in two independent external validation cohorts. The prognostic power of RHL30 was independent of reported clinical prognostic markers (both at initial diagnosis and at relapse) and microenvironmental components as assessed by immunohistochemistry. Conclusion We have developed and validated a novel clinically applicable prognostic assay that at the time of first relapse identifies patients with unfavorable post-ASCT outcomes. Moving forward, it will be critical to evaluate the clinical use of RHL30 in the context of positron emission tomography-guided response assessment and the evolving cHL treatment landscape.

Vrzalikova K, Ibrahim M, Vockerodt M, et al.
S1PR1 drives a feedforward signalling loop to regulate BATF3 and the transcriptional programme of Hodgkin lymphoma cells.
Leukemia. 2018; 32(1):214-223 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
The Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma (HL) are characterised by the aberrant activation of multiple signalling pathways. Here we show that a subset of HL displays altered expression of sphingosine-1-phosphate (S1P) receptors (S1PR)s. S1P activates phosphatidylinositide 3-kinase (PI3-K) in these cells that is mediated by the increased expression of S1PR1 and the decreased expression of S1PR2. We also showed that genes regulated by the PI3-K signalling pathway in HL cell lines significantly overlap with the transcriptional programme of primary HRS cells. Genes upregulated by the PI3-K pathway included the basic leucine zipper transcription factor, ATF-like 3 (BATF3), which is normally associated with the development of dendritic cells. Immunohistochemistry confirmed that BATF3 was expressed in HRS cells of most HL cases. In contrast, in normal lymphoid tissues, BATF3 expression was confined to a small fraction of CD30-positive immunoblasts. Knockdown of BATF3 in HL cell lines revealed that BATF3 contributed to the transcriptional programme of primary HRS cells, including the upregulation of S1PR1. Our data suggest that disruption of this potentially oncogenic feedforward S1P signalling loop could provide novel therapeutic opportunities for patients with HL.

Adams CM, Mitra R, Gong JZ, Eischen CM
Non-Hodgkin and Hodgkin Lymphomas Select for Overexpression of BCLW.
Clin Cancer Res. 2017; 23(22):7119-7129 [PubMed] Article available free on PMC after 30/11/2019 Related Publications

Kuang Z, Guo L, Li X
Identification of key genes and pathways associated with classical Hodgkin lymphoma by bioinformatics analysis.
Mol Med Rep. 2017; 16(4):4685-4693 [PubMed] Article available free on PMC after 30/11/2019 Related Publications
The current study aimed to explore the mechanisms associated with classic Hodgkin lymphoma (cHL) to identify novel diagnostic and therapeutic targets. The GES12453 microarray dataset was downloaded from the Gene Expression Omnibus database; the differentially expressed genes (DEGs) between cHL samples and normal B cell samples by were identified using the limma package. Gene ontology (GO) and pathway enrichment analysis of DEGs gene were performed. Furthermore, construction and analysis of protein‑protein interaction (PPI) network was performed, and co‑expression modules of DEGs were produced. A total of 450 DEGs were identified, comprising 216 upregulated and 234 downregulated genes in cHL compared with normal B cell samples. The DEGs were enriched in biological processes associated with immune response. The upregulated genes were mainly associated with the pathway of transcriptional misregulation in cancer, while downregulated genes were associated with B cell receptor signaling. PPI network analysis demonstrated that IL6 had the highest connectivity degree. Interleukin‑6 (IL6) and signal transducer and activator of transcription 1 (STAT1) were demonstrated to be involved with the response to cytokine GO term in co‑expression module 1. Spleen tyrosine kinase (SYK), B‑cell linker protein (BLNK), CD79B, phospholipase C γ2 (PLCG2) were enriched in the B cell receptor signaling pathway in module 2. Matrix metallopeptidase 9 (MMP9), protein tyrosine phosphatase receptor type C had the highest connectivity degrees in module 3 and module 4, respectively. The results suggested that DEGs, including IL6, STAT1, MMP9, SYK, BLNK, PLCG2 and CD79B, and the pathways of B cell receptor signaling, Epstein‑Barr virus infection and transcriptional misregulation in cancer have strong potential to be useful as targets for diagnosis or treatment of cHL.

Ushmorov A, Wirth T
FOXO in B-cell lymphopoiesis and B cell neoplasia.
Semin Cancer Biol. 2018; 50:132-141 [PubMed] Related Publications
FOX O family transcription factors are important for differentiation and function of multiple cell types. In B lymphocytes they play a critical role. The activity of FOXOs is directly regulated both by signaling from B cell receptor (BCR) and cytokine receptors. FOXO1 action controls the transition between differentiation stages of B cell development. In comparison to other FOXO family members, FOXO1 plays a superior role in the regulation of early stages of B-cell differentiation. Although being known as a negative regulator of cell proliferation and therefore potential tumor suppressor, FOXO1 is downregulated only in Hodgkin lymphoma (HL) subtypes. In non-Hodgkin lymphoma (NHL) entities its expression is maintained at significant levels, raising the question on the role of FOXO-transcription factors in the proliferation and survival programs in the process of B cell differentiation as well as their contribution to the oncogenic programs of B-cell lymphomas. In particular, we discuss molecular mechanisms that might determine the switch between pro-apoptotic and pro-survival effects of FOXO1 and their interplay with specific differentiation programs.

Wang Y, Li Q, Zhu L, et al.
Cytogenetics with flow cytometry in lymph node/extranodal tissue biopsies is sensitive to assist the early diagnosis of suspected lymphomas.
Ann Hematol. 2017; 96(10):1673-1680 [PubMed] Related Publications
Few studies have examined the value of cytogenetic studies with flow cytometry (FC) in lymph node/extranodal tissue biopsies with suspected lymphoma. To evaluate this, G-banded karyotyping and/or fluorescence in situ hybridization (FISH) with FC immunophenotyping were performed on 185 lymph node or extranodal tissue biopsy specimens with suspected lymphoma. Complete cytogenetic analysis of lymph node/extranodal tissue was successful in 174 cases (94.1%) and 57.5% demonstrated chromosomal abnormalities. In 116 malignant lymphoma cases, 83.8% showed abnormalities. In 74 B cell lymphomas (B-NHL), abnormalities were more frequent in lymph node/extranodal tissues than in bone marrow by conventional cytogenetics (CC, 97.2 vs 26.1%), FISH (70.6 vs 17.6%), and FC (98.6 vs 28.4%). Three B-NHL diagnoses were confirmed by re-biopsy of lymph nodes due to the presence of abnormalities in the first biopsy, but no evidence of malignancy in pathological, FC, or IgH/TCR gene rearrangement analyses. In 29 T cell lymphomas (T-NHL), abnormalities were more frequent in lymph nodes than in bone marrow by CC (67.9 vs 21.4%) and FC (75.9 vs 27.6%) analyses. As expected, in 13 Hodgkin lymphoma cases, abnormalities were more frequent in lymph nodes than bone marrow by CC (41.7 vs 16.7%) and FC (30.8 vs 7.7%) analyses. In 56 reactive lymphoid hyperplasias (RLH), 7.1% had conventional clonal cytogenetic abnormalities. Two of these patients died of disease progression and two had their pathological diagnosis revised after the second review. These findings indicate that cytogenetic analysis combined with FC in lymph node/extranodal tissue biopsies can provide critical information in the auxiliary diagnosis of lymphoma.

Borchmann S, Engert A
The genetics of Hodgkin lymphoma: an overview and clinical implications.
Curr Opin Oncol. 2017; 29(5):307-314 [PubMed] Related Publications
PURPOSE OF REVIEW: The goal of this review is to give an overview of the genetics of classical Hodgkin lymphoma. Copy number changes, somatic mutations, genome-wide association studies, changes in gene expression, familial classical Hodgkin lymphoma and epigenetic changes will be reviewed. In doing so, special focus is placed on the way recent discoveries have influenced clinical research, diagnostics, treatment and remission monitoring. Furthermore, emphasis is put on how these advances can help to advance the treatment of elderly patients who have a markedly worse prognosis than younger patients.
RECENT FINDINGS: Frequent amplifications of the 9p24.1 locus in classical Hodgkin lymphoma could be the basis for the success of immune checkpoint inhibitors targeting PD-1 or PD-L1 in this disease. The same amplification also affects the JAK/STAT pathway, which has also been targeted in recent clinical trials. Hodgkin lymphoma-specific copy number alterations and mutations have recently been found to be detectable in cell-free DNA. This could provide the basis for advances in the detection of residual disease during treatment and while monitoring patients in remission.
SUMMARY: The advent of new technologies such as massive parallel sequencing has improved our understanding of the genetics of classical Hodgkin lymphoma. Some of these discoveries are now being translated into clinical research in the form of new diagnostics and treatments.

Lollies A, Hartmann S, Schneider M, et al.
An oncogenic axis of STAT-mediated BATF3 upregulation causing MYC activity in classical Hodgkin lymphoma and anaplastic large cell lymphoma.
Leukemia. 2018; 32(1):92-101 [PubMed] Related Publications
Classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) feature high expression of activator protein-1 (AP-1) transcription factors, which regulate various physiological processes but also promote lymphomagenesis. The AP-1 factor basic leucine zipper transcription factor, ATF-like 3 (BATF3), is highly transcribed in cHL and ALCL; however, its functional importance in lymphomagenesis is unknown. Here we show that proto-typical CD30

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