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.

  • DNA Mutational Analysis
  • B-Cell Lymphoma
  • DNA Sequence Analysis
  • Childhood Cancer
  • Oligonucleotide Array Sequence Analysis
  • MicroRNAs
  • BCL3
  • Epstein-Barr Virus Infections
  • NF-kappa B
  • B-Lymphocytes
  • RTPCR
  • Adolescents
  • Staging
  • FISH
  • Cancer DNA
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Non-Hodgkin Lymphoma
  • Chromosome Aberrations
  • Nuclear Proteins
  • Nucleic Acid Hybridization
  • Polymerase Chain Reaction
  • Diffuse Large B-Cell Lymphoma
  • Hodgkin Lymphoma
  • Base Sequence
  • BCL11A
  • Protein Kinases
  • Neoplasm Proteins
  • Immunohistochemistry
  • Alleles
  • SH2D1A protein, human
  • Gene Expression Profiling
  • Apoptosis
  • Cancer Gene Expression Regulation
  • inosine monophosphate synthase
  • DNA Methylation
  • Proto-Oncogene Proteins
  • Case-Control Studies
  • Mutation
  • Lymph Nodes
  • Genetic Predisposition
  • Genotype
  • CDKN2A
  • Herpesvirus 4, Human
Tag cloud generated 10 March, 2017 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
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
15
CD79A 19q13.2 IGA, MB-1 -CD79A and Hodgkin Lymphoma
14
IL13 5q31 P600, IL-13 -IL13 and Hodgkin Lymphoma
13
CD68 17p13 GP110, LAMP4, SCARD1 -CD68 and Hodgkin Lymphoma
13
STAT6 12q13 STAT6B, STAT6C, D12S1644, IL-4-STAT -STAT6 and Hodgkin Lymphoma
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 19q13.32 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, CT19, 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

Bernig T, Ritz S, Brodt G, et al.
Glutathione-S-transferases and Chemotherapy Resistance of Hodgkin's Lymphoma Cell Lines.
Anticancer Res. 2016; 36(8):3905-15 [PubMed] Related Publications
BACKGROUND: Glutathione-S-transferases (GSTs) are associated with multidrug resistance of tumor cells and are involved in drug detoxification and control of apoptosis. We analyzed the impact of GSTs on apoptosis of Hodgkin's lymphoma (HL) cells.
MATERIALS AND METHODS: Expression of GST isoforms in HL cell lines was assessed by analysis of DNA microarray data and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The impact of the GST inhibitor ethacrynic acid (EA) on HL cell survival was analyzed in vitro.
RESULTS: DNA microarray analysis and qRT-PCR analysis demonstrated higher expression of GST isoforms in chemoresistant HL cells. Therefore, GSTs may contribute to chemoresistance of HL cells. Incubation of GST-expressing chemoresistant L-1236 HL cells with EA significantly enhanced the activity of cisplatin against these cells.
CONCLUSION: Our data suggest that the combined treatment with chemotherapy and GST inhibitors such as EA might be an interesting option for patients with chemoresistant HL.

de Oliveira KA, Kaergel E, Heinig M, et al.
A roadmap of constitutive NF-κB activity in Hodgkin lymphoma: Dominant roles of p50 and p52 revealed by genome-wide analyses.
Genome Med. 2016; 8(1):28 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: NF-κB is widely involved in lymphoid malignancies; however, the functional roles and specific transcriptomes of NF-κB dimers with distinct subunit compositions have been unclear.
METHODS: Using combined ChIP-sequencing and microarray analyses, we determined the cistromes and target gene signatures of canonical and non-canonical NF-κB species in Hodgkin lymphoma (HL) cells.
RESULTS: We found that the various NF-κB subunits are recruited to regions with redundant κB motifs in a large number of genes. Yet canonical and non-canonical NF-κB dimers up- and downregulate gene sets that are both distinct and overlapping, and are associated with diverse biological functions. p50 and p52 are formed through NIK-dependent p105 and p100 precursor processing in HL cells and are the predominant DNA binding subunits. Logistic regression analyses of combinations of the p50, p52, RelA, and RelB subunits in binding regions that have been assigned to genes they regulate reveal a cross-contribution of p52 and p50 to canonical and non-canonical transcriptomes. These analyses also indicate that the subunit occupancy pattern of NF-κB binding regions and their distance from the genes they regulate are determinants of gene activation versus repression. The pathway-specific signatures of activated and repressed genes distinguish HL from other NF-κB-associated lymphoid malignancies and inversely correlate with gene expression patterns in normal germinal center B cells, which are presumed to be the precursors of HL cells.
CONCLUSIONS: We provide insights that are relevant for lymphomas with constitutive NF-κB activation and generally for the decoding of the mechanisms of differential gene regulation through canonical and non-canonical NF-κB signaling.

La Nasa G, Greco M, Littera R, et al.
The favorable role of homozygosity for killer immunoglobulin-like receptor (KIR) A haplotype in patients with advanced-stage classic Hodgkin lymphoma.
J Hematol Oncol. 2016; 9:26 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Interim positron emission tomography after 2 cycles of ABVD (iPET-2) is a good predictor of outcome in advanced-stage classic Hodgkin lymphoma. So far, there are no other prognostic biomarkers capable of identifying chemotherapy refractory patients with comparable accuracy. Despite the considerable amount of evidence suggesting that antitumor immune surveillance is downregulated in classic Hodgkin lymphoma (cHL), few data exist on the impairment of natural killer cell function and the role of their killer immunoglobulin-like receptors (KIRs).
METHODS: We investigated KIR gene frequencies, KIR haplotypes, and KIR-ligand combinations in a cohort of 135 patients with advanced-stage classic Hodgkin lymphoma and 221 healthy controls. We furthermore evaluated the correlation of KIR genes and KIR haplotypes with the achievement of negative iPET-2.
RESULTS: In the cohort of patients, the 5-year overall survival and progression-free survival were 93.6 and 79%, respectively. Homozygosity for KIR A haplotype and the HLA-C1 KIR ligand (KIR-AA/C1C1) was significantly higher in healthy controls (15.7 vs. 4.8%, p = 0.001). The KIR-AA genotype resulted to have a significant predictive power for achieving iPET-2 negativity (p = 0.039).
CONCLUSIONS: Homozygosity for KIR A haplotype offers protection against classic Hodgkin lymphoma. The association found for the KIR-AA genotype and achievement of negative iPET-2 suggests that KIR-AA could be used in clinical practice to enhance the chemosensitivity predictive power of iPET-2. Our results point to the possibility of adapting treatment strategies based on the combination of KIR biomarkers and PET scan.

Paydas S, Acikalin A, Ergin M, et al.
Micro-RNA (miRNA) profile in Hodgkin lymphoma: association between clinical and pathological variables.
Med Oncol. 2016; 33(4):34 [PubMed] Related Publications
miRNAs are small RNAs and control the expression of protein-encoding genes. The aim of this study was to determine the association between miRNA profile and clinical variables including age, stage, B symptom, histopathologic subtype, response to treatment, disease-free survival (DFS) and overall survival (OS) in classical Hodgkin lymphoma (cHL). A total of 377 miRNAs were studied by qPCR in 32 cases with cHL, and results were compared with 60 samples taken from cases with reactive lymphadenopathy. Biogazelle qbasePLUS 2.0 software was used to analyze the results. miR-582-3p, miR-525-3p, miR-448, miR-512-3p, miR-642a-5p, miR-876-5p, miR-532-3p, miR-654-5p, miR-128, miR-145-5p, miR-15b-5p, miR-328 and miR-660-5p were found to be decreased in cHL compared with controls. In contrast, miR-34a-5p (2.626-fold), miR-146a-5p (4.32-fold), miR-93-5p (2.347-fold), miR-20a-5p (4.930-fold), miR-339-3p (4.948-fold), miR-324-3p (4.98-fold), miR-372 (7.038-fold), miR-127-3p (8.234-fold), miR-155-5p (4.947-fold), miR-320a (17.502-fold) and miR-370 (21.479-fold) (p < 0.05) were found to be increased in cHL. There was no difference in miRNA profile according to the age, sex, stage, response to treatment, DFS and OS. However, miR-889 was found to be increased in patients with B symptom and miR-127-3p was found to be increased in nodular sclerosing subtype. Some miRNAs increase and some decrease in cHL. However, there was no clinical association between clinical variables and with the majority of the miRNA profile studied in this study. miR-889 and miR-127-3p were related to B symptom and nodular sclerosis subtype, respectively. We need more studies evaluating miRNA profile and clinical outcome in Hodgkin Lymphoma.

Hartmann S, Schuhmacher B, Rausch T, et al.
Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma.
Leukemia. 2016; 30(4):844-53 [PubMed] Related Publications
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)-a subtype of Hodgkin lymphoma (HL)-is characterized by a low content of tumor cells, the lymphocyte predominant (LP) cells. Transformation into diffuse large B-cell lymphoma (DLBCL) occurs in about 10% of patients. We performed whole-genome mutation analysis of the DLBCL components from two composite lymphomas consisting of clonally related NLPHL and DLBCL as a means to identify candidate tumor suppressor genes and oncogenes in NLPHL. The analysis of LP cells for selected mutations of the DLBCL revealed that most mutations are also present in the LP cells, indicating a close relationship between the two components. The analysis of 62 selected genes in NLPHL by targeted ultra-deep sequencing revealed three novel highly recurrently mutated genes (each mutated in ~50% of cases), that is, DUSP2, SGK1 and JUNB. SGK1 was expressed in the LP cells of primary NLPHL cases and in the NLPHL cell line DEV. Administration of an SGK1 inhibitor induced apoptosis in the NLPHL cell line DEV and the DLBCL cell line Farage, suggesting a pathogenetic role of SGK1 in the LP and DLBCL cells. In summary, the present study identifies SGK1, DUSP2 and JUNB as novel key players in the pathogenesis of NLPHL.

Salipante SJ, Adey A, Thomas A, et al.
Recurrent somatic loss of TNFRSF14 in classical Hodgkin lymphoma.
Genes Chromosomes Cancer. 2016; 55(3):278-87 [PubMed] Free Access to Full Article Related Publications
Investigation of the genetic lesions underlying classical Hodgkin lymphoma (CHL) has been challenging due to the rarity of Hodgkin and Reed-Sternberg (HRS) cells, the pathognomonic neoplastic cells of CHL. In an effort to catalog more comprehensively recurrent copy number alterations occurring during oncogenesis, we investigated somatic alterations involved in CHL using whole-genome sequencing-mediated copy number analysis of purified HRS cells. We performed low-coverage sequencing of small numbers of intact HRS cells and paired non-neoplastic B lymphocytes isolated by flow cytometric cell sorting from 19 primary cases, as well as two commonly used HRS-derived cell lines (KM-H2 and L1236). We found that HRS cells contain strikingly fewer copy number abnormalities than CHL cell lines. A subset of cases displayed nonintegral chromosomal copy number states, suggesting internal heterogeneity within the HRS cell population. Recurrent somatic copy number alterations involving known factors in CHL pathogenesis were identified (REL, the PD-1 pathway, and TNFAIP3). In eight cases (42%) we observed recurrent copy number loss of chr1:2,352,236-4,574,271, a region containing the candidate tumor suppressor TNFRSF14. Using flow cytometry, we demonstrated reduced TNFRSF14 expression in HRS cells from 5 of 22 additional cases (23%) and in two of three CHL cell lines. These studies suggest that TNFRSF14 dysregulation may contribute to the pathobiology of CHL in a subset of cases.

Kuhlen M, Hönscheid A, Schemme J, et al.
Hodgkin lymphoma as a novel presentation of familial DICER1 syndrome.
Eur J Pediatr. 2016; 175(4):593-7 [PubMed] Related Publications
UNLABELLED: DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly presenting with pleuropulmonary blastoma (PPB), ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. We describe the occurrence of a Hodgkin lymphoma (HL) of the T cell phenotype in a family with DICER1 syndrome. The patient presented with PPB Type I and HL. Immunohistochemical staining of the Hodgkin and Reed-Sternberg cells revealed CD30, TGP, CD2, CD3, CD15, and IRF4 positivity and weekly positivity of PAX5. T cell receptor repertoire analysis suggested HL of T cell origin, which is in contrast to common B cell-derived HL. The mother had been diagnosed with thyroid cysts, one sister had died from a primitive neuroectodermal tumor, and a brother had died from PPB Type III. Two mutational events were revealed in all affected family members; a single bp deletion, c.5299delC, leading to a frameshift and premature stop in exon 24 and a heterozygous variant (c.4616C>T; p.Thr1539Met) located in exon 23 of the DICER1 gene. This variant is predicted to be benign by in silico analysis.
CONCLUSION: Future studies looking for DICER1 mutations in HL cases of the T cell phenotype will be important to confirm its association with constitutional DICER1 syndrome.
WHAT IS KNOWN: • DICER1 germline mutations are associated with an inherited cancer syndrome, most commonly pleuropulmonary blastoma, ovarian sex cord tumors, thyroid cysts/goitre, and cystic nephroma. • Hodgkin lymphoma is one of the most frequent types of malignant lymphomas and typically arises sporadically. T cell-derived Hodgkin lymphomas are exceptionally rare. What is New: • DICER1 syndrome may have an even broader phenotypic spectrum and seems to be associated with rare forms of T cell Hodgkin lymphoma.

Slezak-Prochazka I, Kluiver J, de Jong D, et al.
Inhibition of the miR-155 target NIAM phenocopies the growth promoting effect of miR-155 in B-cell lymphoma.
Oncotarget. 2016; 7(3):2391-400 [PubMed] Free Access to Full Article Related Publications
Several studies have indicated an important role for miR-155 in the pathogenesis of B-cell lymphoma. Highly elevated levels of miR-155 were indeed observed in most B-cell lymphomas with the exception of Burkitt lymphoma (BL). However, the molecular mechanisms that underlie the oncogenic role of miR-155 in B-cell lymphoma are not well understood. To identify the miR-155 targets relevant for B-cell lymphoma, we performed RNA immunoprecipitation of Argonaute 2 in Hodgkin lymphoma (HL) cells upon miR-155 inhibition and in BL cells upon ectopic expression of miR-155. We identified 54 miR-155-specific target genes in BL cells and confirmed miR-155 targeting of DET1, NIAM, TRIM32, HOMEZ, PSIP1 and JARID2. Five of these targets are also regulated by endogenous miR-155 in HL cells. Both overexpression of miR-155 and inhibition of expression of the novel miR-155 target gene NIAM increased proliferation of BL cells. In primary B-cell lymphoma NIAM-positive cases have significant lower levels of miR-155 as compared to NIAM-negative cases, suggesting that NIAM is also regulated by miR-155 in primary B-cell lymphoma. Thus, our data indicate an oncogenic role for miR-155 in B-cell lymphoma which involves targeting the tumor suppressor NIAM.

Ghorbian S, Jahanzad I, Estiar MA, et al.
Molecular Analysis of IGH and Incomplete IGH D-J Clonality Gene Rearrangements in Hodgkin Lymphoma Malignancies.
Clin Lab. 2015; 61(8):951-5 [PubMed] Related Publications
BACKGROUND: We evaluated molecular clonality in immunoglobulin heavy chain (IGH) and incomplete IGH D-J genes for improvement of clinical diagnosis of Hodgkin's lymphoma (HL). We applied BIOMED-2 protocols in HL cases, which were previously approved by clonality detection in non-Hodgkin lymphoma (NHL) cases.
METHODS: We investigated 50 consecutive FFPE samples of classical HL (cHL) patients to assess IGH and IGH D-J clonal gene rearrangements by multiplex PCR protocols, which were provided by the European Biomedicine and Health (BIOMED-2) Concerted Action Project BMH4-CT98-3936.
RESULTS: In the present study, there was a monoclonality of 86% (43/50) including a clonality of 74% (37/50) for IGH and a clonality of 42% (21/50) in IGHD-J. In addition, a lack of clonality was detected in 14% (7/50) of cases. Frequent gene rearrangements were detected in framework (FR) III (54%) and FRII (20%), whereas no clonality was seen in FRI. Furthermore, a monoclonality of 28% and 14% was detected in the DH(1-6)-JH and DH(see symbol)-JH gene rearrangements, respectively.
CONCLUSIONS: The present study suggests that the complete IGH and incomplete IGH D-J clonality gene rearrangement assays using BIOMED-2 protocols could be considered a valuable method for detection of clonal gene rearrangements, especially in HL cases.

Nagel S, Ehrentraut S, Meyer C, et al.
Aberrantly Expressed OTX Homeobox Genes Deregulate B-Cell Differentiation in Hodgkin Lymphoma.
PLoS One. 2015; 10(9):e0138416 [PubMed] Free Access to Full Article Related Publications
In Hodgkin lymphoma (HL) we recently reported that deregulated homeobox gene MSX1 mediates repression of the B-cell specific transcription factor ZHX2. In this study we investigated regulation of MSX1 in this B-cell malignancy. Accordingly, we analyzed expression and function of OTX homeobox genes which activate MSX1 transcription during embryonal development in the neural plate border region. Our data demonstrate that OTX1 and OTX2 are aberrantly expressed in both HL patients and cell lines. Moreover, both OTX loci are targeted by genomic gains in overexpressing cell lines. Comparative expression profiling and subsequent pathway modulations in HL cell lines indicated that aberrantly enhanced FGF2-signalling activates the expression of OTX2. Downstream analyses of OTX2 demonstrated transcriptional activation of genes encoding transcription factors MSX1, FOXC1 and ZHX1. Interestingly, examination of the physiological expression profile of ZHX1 in normal hematopoietic cells revealed elevated levels in T-cells and reduced expression in B-cells, indicating a discriminatory role in lymphopoiesis. Furthermore, two OTX-negative HL cell lines overexpressed ZHX1 in correlation with genomic amplification of its locus at chromosomal band 8q24, supporting the oncogenic potential of this gene in HL. Taken together, our data demonstrate that deregulated homeobox genes MSX1 and OTX2 respectively impact transcriptional inhibition of (B-cell specific) ZHX2 and activation of (T-cell specific) ZHX1. Thus, we show how reactivation of a specific embryonal gene regulatory network promotes disturbed B-cell differentiation in HL.

Oelmann E, Stein H, Berdel WE, Herbst H
Expression of Interleukin-1 and Interleukin-1 Receptors Type 1 and Type 2 in Hodgkin Lymphoma.
PLoS One. 2015; 10(9):e0138747 [PubMed] Free Access to Full Article Related Publications
Signaling through the IL-1-receptor type 1 (IL-1R1), IL-1 is required for initiation and maintenance of diverse activities of the immune system. A second receptor, IL-1R2, blocks IL-1 signal transduction. We studied expression of IL-1beta, IL-1R1, and IL-1R2 in 17 Hodgkin lymphomas (HL) by in situ hybridization (ISH). IL-1beta expressing cells, morphologically consistent with endothelial cells and fibroblasts, occurred in all HL tissues with elevated transcript levels in areas of active fibrosis. Hodgkin and Reed-Sternberg (HRS) cells of all cases expressed low IL-1R1 transcript levels in some tumor cells, and high levels of IL-1R2 in large proportions of HRS cells. Only few bystander cells showed low levels of IL-1R1 and IL-1R2 RNA. Supernatants of 4 out of 7 HL-derived cell lines contained soluble IL-1R2 protein at high levels. HL patient sera carried variably amounts of IL-1R2 protein with significantly increased titers in patients with active disease compared to patients in complete remission and control individuals without HL. Western blots and co-immunoprecipitations showed binding of the IL-1R2 to the intracellular IL-1R-accessory protein (IL-1IRAcP). These data suggest functions of the IL-1R2 as a "decoy-receptor" sequestrating paracrine IL-1 extracellularly and intracellularly by engaging IL-1IRAcP, thus depriving IL1-R1 molecules of their extracellular and intracellular ligands. Expression of IL1-R2 by HRS cells seems to contribute to local and systemic modulation of immune function in HL.

Delahaye-Sourdeix M, Urayama KY, Gaborieau V, et al.
A Novel Risk Locus at 6p21.3 for Epstein-Barr Virus-Positive Hodgkin Lymphoma.
Cancer Epidemiol Biomarkers Prev. 2015; 24(12):1838-43 [PubMed] Related Publications
BACKGROUND: A proportion of the genetic variants involved in susceptibility to Hodgkin lymphoma differ by the tumor's Epstein-Barr virus (EBV) status, particularly within the MHC region.
METHODS: We have conducted an SNP imputation study of the MHC region, considering tumor EBV status in 1,200 classical Hodgkin lymphoma (cHL) cases and 5,726 control subjects of European origin. Notable findings were genotyped in an independent study population of 468 cHL cases and 551 controls.
RESULTS: We identified and subsequently replicated a novel association between a common genetic variant rs6457715 and cHL. Although strongly associated with EBV-positive cHL [OR, 2.33; 95% confidence interval (CI), 1.83-2.97; P = 7 × 10(-12)], there was little evidence for association between rs6457715 and the EBV-negative subgroup of cHL (OR, 1.06; 95% CI, 0.92-1.21), indicating that this association was specific to the EBV-positive subgroup (Phet < P = 10(-8)). Furthermore, the association was limited to EBV-positive cHL subgroups within mixed cell (MCHL) and nodular sclerosis subtypes (NSHL), suggesting that the association is independent of histologic subtype of cHL.
CONCLUSIONS: rs6457715, located near the HLA-DPB1 gene, is associated with EBV-positive cHL and suggests this region as a novel susceptibility locus for cHL.
IMPACT: This expands the number of genetic variants that are associated with cHL and provides additional evidence for a critical and specific role of EBV in the etiology of this disease.

Sud A, Cooke R, Swerdlow AJ, Houlston RS
Genome-wide homozygosity signature and risk of Hodgkin lymphoma.
Sci Rep. 2015; 5:14315 [PubMed] Free Access to Full Article Related Publications
Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing Hodgkin lymphoma (HL) we analysed 589 HL cases and 5,199 controls genotyped for 484,072 tag single nucleotide polymorphisms (SNPs). Across the genome the cumulative distribution of ROH was not significantly different between cases and controls. Seven ROH at 4q22.3, 4q32.2, 7p12.3-14.1, 7p22.2, 10p11.22-23, 19q13.12-2 and 19p13.2 were associated with HL risk at P < 0.01. Intriguingly 4q22.3 harbours an ROH to which the nuclear factor NF-kappa-B p105 subunit (NFKB1) maps (P = 0.002). The ROH at 19q13.12-2 has previously been implicated in B-cell precursor acute lymphoblastic leukaemia. Aside from these observations which require validation, it is unlikely that levels of measured homozygosity caused by autozygosity, uniparental isodisomy or hemizygosity play a major role in defining HL risk in predominantly outbred populations.

Dhiab MB, Ziadi S, Mestiri S, et al.
DNA methylation patterns in EBV-positive and EBV-negative Hodgkin lymphomas.
Cell Oncol (Dordr). 2015; 38(6):453-62 [PubMed] Related Publications
PURPOSE: Hodgkin lymphoma (HL) is characterized by the presence of Hodgkin and Reed-Sternberg cells. Epstein-Barr virus (EBV) infection is thought to play an important role in the development of HL. Although epigenetic alterations, such as aberrant DNA methylation, are known to contribute to the pathogenesis of various malignancies, little is known about such alterations in HL and their putative relationships with EBV infection.
METHODS: We investigated promoter methylation patterns of seven tumor-associated genes in 53 primary HL cases using methylation-specific PCR (MS-PCR). Concomitantly, the EBV infection status was assessed using PCR, in situ hybridization and immunohistochemistry.
RESULTS: The gene promoter hypermethylation frequencies observed were 77.3 % for P16, 58.5 % for RASSF1A, 50.9 % for CDH1, 45.3 % for DAPK, 43.4 % for GSTP1, 37.7 % for SHP1 and 24.3 % for MGMT. SHP1 gene promoter hypermethylation was more frequently observed in patients at extreme ages (i.e., ≤ 15 and >54 years) than in adult patients (p = 0.006) and in patients with B symptoms (p = 0.03). Interestingly, most of the analyzed gene promoters were more frequently hypermethylated in EBV-negative than in EBV-positive cases, in particular the DAPK gene promoter (58 % versus 27 %, p = 0.04). Furthermore, hypermethylation of multiple gene promoters (≥ 3) was encountered more frequently in females than in males (86 % versus 57 %, p = 0.04), whereas EBV-positive cases were more common among males than females (55 % versus 30 %, p = 0.02).
CONCLUSIONS: Our results indicate that epigenetic changes frequently occur in both EBV-positive and EBV-negative HL. The rates of these changes were found to vary according to clinico-pathological parameters. These observations probably reflect the multitude of factors involved in HL development and the complexity of their interactions with genetic and/or hormonal factors.

Ben Dhiab M, Ziadi S, Louhichi T, et al.
Investigation of miR9-1, miR9-2 and miR9-3 Methylation in Hodgkin Lymphoma.
Pathobiology. 2015; 82(5):195-202 [PubMed] Related Publications
BACKGROUND: miR9 is an important tumor suppressor microRNA regulated by DNA methylation in various types of cancers.
METHODS: We analyzed the methylation status of the 3 members of the miR9 family in 58 cases of Hodgkin lymphoma (HL) in comparison to 15 reactive lymph nodes. We also assessed the relationships between miR9 methylation and Epstein-Barr virus (EBV) infection and several clinicopathological parameters.
RESULTS: We found that 84.5% of HL cases had a methylation in at least 1 of the 3 loci of miR9, whereas none of the nontumoral samples was methylated. The highest rate of methylation was found in miR9-2 (5q14.3) in 74.1% of the HL cases, followed by miR9-3 (15q26.1) in 56.9% and miR9-1 (1q22) in only 8.6% (p < 0.001). The promoter methylation of miR9-3 was more frequent in patients older than 15 years than in children (p = 0.02) and among women rather than men (p = 0.02). However, no significant correlation was found between miR9 methylation and EBV infection.
CONCLUSION: These results indicate that miR9 methylation, especially miR9-2, is a frequent event in HL and may be involved in HL pathogenesis, irrespective of EBV infection.

Lennerz JK, Hoffmann K, Bubolz AM, et al.
Suppressor of cytokine signaling 1 gene mutation status as a prognostic biomarker in classical Hodgkin lymphoma.
Oncotarget. 2015; 6(30):29097-110 [PubMed] Free Access to Full Article Related Publications
Suppressor of cytokine signaling 1 (SOCS1) mutations are among the most frequent somatic mutations in classical Hodgkin lymphoma (cHL), yet their prognostic relevance in cHL is unexplored. Here, we performed laser-capture microdissection of Hodgkin/Reed-Sternberg (HRS) cells from tumor samples in a cohort of 105 cHL patients. Full-length SOCS1 gene sequencing showed mutations in 61% of all cases (n = 64/105). Affected DNA-motifs and mutation pattern suggest that many of these SOCS1 mutations are the result of aberrant somatic hypermutation and we confirmed expression of mutant alleles at the RNA level. Contingency analysis showed no significant differences of patient-characteristics with HRS-cells containing mutant vs. wild-type SOCS1. By predicted mutational consequence, mutations can be separated into those with non-truncating point mutations ('minor' n = 49/64 = 77%) and those with length alteration ('major'; n = 15/64 = 23%). Subgroups did not differ in clinicopathological characteristics; however, patients with HRS-cells that contained SOCS1 major mutations suffered from early relapse and significantly shorter overall survival (P = 0.03). The SOCS1 major status retained prognostic significance in uni-(P = 0.016) and multivariate analyses (P = 0.005). Together, our data indicate that the SOCS1 mutation type qualifies as a single-gene prognostic biomarker in cHL.

Galleze A, Raache R, Amroun H, et al.
HLA Polymorphism in Algerian Children With Lymphomas.
J Pediatr Hematol Oncol. 2015; 37(8):e458-61 [PubMed] Related Publications
BACKGROUND: Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) are the 2 types of lymphoma that represent the third most common childhood malignancy. Multiple etiological factors are involved in lymphoma pathogenesis, including viral infection, immune deficiencies, environmental agents, and genetic factors. Strong arguments supporting a genetic linkage between the susceptibility to lymphomas and human leukocyte antigens (HLA) are reported and give an idea about susceptibility or protection from the disease.
METHODS: Seventy-one cases were included in this study: 36 cases of non-Hodgkin lymphoma and 35 patients with Hodgkin lymphoma. Their ages ranged from 4 to 18 years. The control group consisted of 70 unrelated healthy individuals, with a mean age of 5 to 17 years. The genotype of HLA-A, HLA-B, HLA-DR, and HLA-DQ alleles was typed by means of PCR sequence-specific priming.
RESULTS: HLA-B*18, HLA-DRB1*03, *07, and HLA-DQB1*02 were significantly increased in patients with lymphomas when compared with controls, whereas HLA-DRB1*13 and DQB1*03 were significantly decreased when compared with controls.
CONCLUSIONS: These results indicate that HLA-B*18, DRB1*03, *07, and DQB1*02 may contribute to lymphoma susceptibility, whereas HLA-DRB1*13 and DQB1*03 may confer protection to lymphoma in the Algerian population.

Kharazmi E, Fallah M, Pukkala E, et al.
Risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex: a joint study from five Nordic countries.
Blood. 2015; 126(17):1990-5 [PubMed] Related Publications
We aimed to provide the familial risk of classical Hodgkin lymphoma (HL) by relationship, histology, age at diagnosis, and sex. A cohort of 57,475 first-degree relatives of 13,922 HL patients diagnosed between 1955 and 2009 in 5 European countries was observed for HL incidence. The overall lifetime cumulative risk (CR) of HL in first-degree relatives of a patient with HL was 0.6%, which represents a threefold (standardized incidence ratio [SIR], 3.3; 95% confidence interval [CI], 2.8-3.9) increased risk over the general population risk. The risk in siblings (6.0-fold; 95% CI, 4.8- to 7.4-fold) was significantly higher than in parents and/or children (2.1-fold; 95% CI, 1.6- to 2.6-fold). Very high lifetime risk of HL was found for those with multiple affected first-degree relatives (13-fold; 95% CI, 2.8- to 39-fold) and for same-sex twins (57-fold; 95% CI, 21- to 125-fold). We found high familial risks between some concordant histologic subtypes of HL such as lymphocyte-rich (81-fold; 95% CI, 30- to 177-fold) and nodular sclerosis (4.6-fold; 95% CI, 2.9- to 7.0-fold) and also between some discordant subtypes. The familial risk in sisters (9.4-fold; 95% CI, 5.9- to 14-fold) was higher than in brothers (4.5-fold; 95% CI, 2.9- to 6.7-fold) or unlike-sex siblings (5.9-fold; 95% CI, 4.3- to 8.1-fold). The lifetime risk of HL was higher when first-degree relatives were diagnosed at early ages (before age 30 years). This study provides tangible absolute risk estimates for relatives of HL patients, which can be used as a sex-, age-, and family history-based risk calculator for classical HL by oncologists and genetic counselors.

da Silva PB, Perini GF, Pereira Lde A, et al.
Imbalance of Pro- and Anti-Inflammatory Cytokines in Patients With cHL Persists Despite Treatment Compared With Control Subjects.
Clin Lymphoma Myeloma Leuk. 2015; 15 Suppl:S151-7 [PubMed] Related Publications
BACKGROUND: Classical Hodgkin lymphoma (cHL) is a malignant lymphoma that most commonly affects young adults. The lymphomagenesis of cHL depends largely on immune alterations that contribute to proliferation and maintenance of the Hodgkin-Reed-Sternberg (HRS) neoplastic cells. A combination of different immune processes is responsible for the escape of HRS cells, the imbalance between pro- and anti-inflammatory cytokines being one of them. In this study, we aimed to measure serum levels of pro- and anti-inflammatory cytokines in cHL patients before and after treatment compared with a healthy controls group, and to investigate associations with clinical and pathologic characteristics.
PATIENTS AND METHODS: We prospectively studied all cases of cHL diagnosed between March 2009 to March 2013 at the Universidade Federal de São Paulo and Hospital Santa Marcelina, in Sao Paulo, Brazil. Twenty-nine cases with sufficient clinical data were included in this study. Additionally, 18 healthy control subjects were included and recruited from our University Blood Bank. Serum cytokine levels of interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor (TNF)-α, soluble IL-2 receptor (sCD25), vascular endothelial growth factor (VEGF), and interferon (IFN)-γ were determined in serum of patients and controls using a multiplexed immunoassay system.
RESULTS: Higher International Prognostic Score was positively correlated with increased levels of IL-6 (P = .003); sCD25 levels were higher in patients with low serum albumin (P = .04), and IFN-γ seemed to correlate with B symptoms, although did not reach statistical significance (P = .057). Pretreatment levels of IL-10, IL-6, TNF-α, and sCD25 were increased in cHL patients compared with in healthy control subjects (P < .001), with median values of 7 pg/mL (range, 0.3-230.9), 5.3 pg/mL (range, 0.4-72.7), 14.6 (range, 4.0-60.4), and 575.9 pg/mL (range, 7.5-1813.3), respectively. Treatment significantly reduced levels of IL-10 (7.0 to 0.3; P < .001), IL-6 (5.3 to 0.4; P = .014), and sCD25 (575.9 to 93.5; P < .001), however, levels of IL-4 increased (0.6 to 2.2; P = .002). Compared with normal control subjects, increased levels of IL-6 (0.4 to 0.4; P = .027), sCD25 (93.5 to 7.5; P = .002), and TNF-α (12 to 8.7; P = .003) persisted after treatment.
CONCLUSION: In this study we showed higher levels of IL-6, IL-10, TNF-α, and sCD25 in cHL patients at diagnosis than in healthy control subjects. After treatment, levels of IL-6, IL-10, and sCD25 decreased gradually but did not normalize. Understanding the cytokine pattern is extremely important in the development of future therapies that target interactions between neoplastic cells and the inflammatory microenvironment.

Caliò A, Zamò A, Ponzoni M, et al.
Cellular Senescence Markers p16INK4a and p21CIP1/WAF Are Predictors of Hodgkin Lymphoma Outcome.
Clin Cancer Res. 2015; 21(22):5164-72 [PubMed] Related Publications
PURPOSE: There is evidence that Hodgkin Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) could display some molecular and morphologic markers of cellular senescence (CS). We hypothesized that CS mechanisms may have potential prognostic relevance in cHL and investigated whether the expression of the well-established CS biomarkers p21(CIP1/WAF1) and p16(INK4a) by HRS cells might be predictive of the probability of event-free survival (EFS).
EXPERIMENTAL DESIGN: The study analyzed a retrospective cohort of 147 patients and the results were validated on a cohort of 91 patients independently diagnosed and treated in a different institution. p16(INK4a) and p21(CIP1/WAF1) were categorized as dichotomous variables (< or ≥ 30% of HRS cells at diagnosis) and evaluated in univariate and multivariate analysis.
RESULTS: Both molecules were independent prognostic factors. A positive staining of one of the two molecules in more than 30% HRS cells predicted a better EFS (P < 0.01). p16(INK4a)/p21(CIP1/WAF1) together as a unique categorical variable (both <30%, either <30%, both ≥ 30%) sorted out three prognostic groups with better, intermediate, or worse outcome either overall or within I-II, bulky and advanced stages. The presence or the lack of the robust expression of p21(CIP1/WAF1) and/or p16(INK4a) defined the prognosis in our series.
CONCLUSIONS: These findings point to (i) the relevance of CS-related mechanisms in cHL, and to (ii) the prognostic value of a simple, reproducible, and low-cost immunohistochemical evaluation of p16(INK4a) and p21(CIP1/WAF1) expression.

Schneider M, Schneider S, Zühlke-Jenisch R, et al.
Alterations of the CD58 gene in classical Hodgkin lymphoma.
Genes Chromosomes Cancer. 2015; 54(10):638-45 [PubMed] Related Publications
Immune evasion plays a central role in the pathophysiology of classical Hodgkin lymphoma (cHL). As mutations of the CD58 gene contribute to immune evasion of diffuse large B cell lymphoma tumor cells, we studied whether alterations of the CD58 gene also occur in Hodgkin and Reed/Sternberg (HRS) cells of cHL. Single nucleotide polymorphism chip analysis revealed homozygous deletions within the CD58 gene in two cHL cell lines (SUP-HD1 and U-HO1). Sequencing of the CD58 gene in seven cHL cell lines disclosed in addition a homozygous splice site mutation in cell line KM-H2. None of the three mutated lines expressed CD58 protein on their surface. Thus, three of seven cHL cell lines analyzed harbor destructive CD58 mutations. Molecular analysis of isolated HRS cells from 10 primary cases of cHL; however, did not reveal any case with a CD58 mutation. A FICTION study indicated heterozygous deletions of CD58 in 3 of 13 cHL analyzed. Overall, we report frequent inactivating mutations of CD58 in cHL cell lines, but their rare occurrence in primary HRS cells. As the three cHL cell lines with CD58 mutations were all established from HRS cells located in pleural effusions, i.e., outside the normal lymph node microenvironment, in end-stages of the disease, CD58 inactivation in cHL might be predominantly prevalent to such situations.

McAulay KA, Jarrett RF
Human leukocyte antigens and genetic susceptibility to lymphoma.
Tissue Antigens. 2015; 86(2):98-113 [PubMed] Related Publications
Familial aggregation, coupled with ethnic variation in incidence, suggests that inherited susceptibility plays a role in the development of lymphoma, and the search for genetic risk factors has highlighted the contribution of the human leukocyte antigen (HLA) complex. In a landmark study published almost 50 years ago, Hodgkin lymphoma (HL) was the first disease to be associated with HLA variation. It is now clear that Epstein-Barr virus (EBV)-positive and -negative HL are strongly associated with specific HLA polymorphisms but these differ by EBV status of the tumours. HLA class I alleles are consistently associated with EBV-positive HL while a polymorphism in HLA class II is the strongest predictor of risk of EBV-negative HL. Recent investigations, particularly genome-wide association studies (GWAS), have also revealed associations between HLA and common types of non-Hodgkin lymphoma (NHL). Follicular lymphoma is strongly associated with two distinct haplotypes in HLA class II whereas diffuse large B-cell lymphoma is most strongly associated with HLA-B*08. Although chronic lymphocytic leukaemia is associated with variation in HLA class II, the strongest signals in GWAS are from non-HLA polymorphisms, suggesting that inherited susceptibility is explained by co-inheritance of multiple low risk variants. Associations between B-cell derived lymphoma and HLA variation suggest that antigen presentation, or lack of, plays an important role in disease pathogenesis but the precise mechanisms have yet to be elucidated.

Tesi B, Chiang SC, El-Ghoneimy D, et al.
Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations.
Pediatr Blood Cancer. 2015; 62(12):2094-100 [PubMed] Related Publications
BACKGROUND: Perforin, encoded by PRF1, is a pore-forming protein crucial for lymphocyte cytotoxicity. Biallelic PRF1 nonsense mutations invariably result in early-onset hemophagocytic lymphohistiocytosis (HLH), termed familial HLH type 2 (FHL2). In contrast, biallelic PRF1 missense mutations may give rise to later-onset disease and more variable manifestations.
PROCEDURE: We retrospectively searched our database for patients from families with siblings carrying biallelic PRF1 missense mutations where at least one sibling did not develop HLH, and for patients with biallelic PRF1 missense mutations and an atypical presentation of disease. We reviewed their clinical, genetic, and immunological characteristics.
RESULTS: In all, we identified 10 such patients, including three sibling pairs with discordant manifestations. Interestingly, in two families, siblings of late-onset HLH patients developed Hodgkin lymphoma but no HLH. In a third family, one sibling presented with recurrent HLH episodes, whereas the other remains healthy. Of note, the affected sibling also suffered from systemic lupus erythematosus. Additional unrelated patients with biallelic PRF1 missense mutations were affected by neurological disease without classical signs of HLH, gastrointestinal inflammation as initial presentation of disease, as well as a hematological malignancy. Compared to early-onset FHL2 patients, the patients with an atypical presentation displayed a partial recovery of NK cell cytotoxicity upon IL-2 stimulation in vitro.
CONCLUSIONS: Our findings substantiate and expand the spectrum of clinical presentations of perforin deficiency, linking PRF1 missense mutations to lymphoma susceptibility and highlighting clinical variability within families. PRF1 mutations should, therefore, be considered as a cause of several diseases disparate to HLH.

Ghorbian S, Jahanzad I, Javadi GR, Sakhinia E
Evaluation of IGK and IGL molecular gene rearrangements according to the BIOMED-2 protocols for clinical diagnosis of Hodgkin lymphoma.
Hematology. 2016; 21(3):133-7 [PubMed] Related Publications
BACKGROUND: Although the analysis of molecular clonality rearrangements of the immunoglobulin light chains (IGK and IGL) is an alternative approach for diagnosis of B cell non-Hodgkin lymphomas (NHLs) using BIOMED-2 protocols, NHLs have not been extensively confirmed for Hodgkin lymphoma (HL) cases. We evaluated BIOMED-2 protocols in HL cases, which have been suggested previously as gold standard method for molecular clonality analysis on formalin fixed, paraffin-embedded (FFPE) tissue in NHL patients.
METHODS: We recruited 50 consecutive FFPE tissues of HL samples to evaluate IGK and IGL clonality gene rearrangements using BIOMED-2 and Heteroduplex methods.
RESULTS: Our findings revealed a total of 94% (47/50) positive clonality, which consisted of 70% (35/50) for IGK and 44% (22/50) for IGL. In three cases, clonality was not detected in any of the immunoglobulin gene segments.
CONCLUSIONS: Analysis of clonality gene rearrangements in IGK and IGL genes using BIOMED-2 protocols could be implemented as a valuable method for improving clonality detection rate in HL cases and sensitivity (94%) and accuracy of HL diagnosis similar to that of the NHL samples will be increased.

Chen DY, Crawford JR
Hodgkin's lymphoma in an adolescent previously treated with surgical resection of third ventricular juvenile pilocytic astrocytoma.
BMJ Case Rep. 2015; 2015 [PubMed] Related Publications
We present a case of a 19-year-old man with cervical lymphadenopathy diagnosed with classical Hodgkin's lymphoma 9 years after gross total resection of a third ventricular juvenile pilocytic astrocytoma (JPA). Chemotherapy or radiation therapy was not a part of his initial JPA treatment. Owing to his two primary neoplasms, genetic testing was performed, which revealed heterozygous polymorphisms of unknown significance for CDH1 and p53, and negative BRAF mutation analysis. Our case reports development of classical Hodgkin's lymphoma after JPA in the absence of antecedent radiation and/or chemotherapy, and identifiable genetic predisposition.

Alme C, Satwani P, Alobeid B, et al.
Atypical Clinical Course in Pediatric Hodgkin Lymphoma: Association With Germline Mutations in Interleukin-2-inducible T-Cell Kinase.
J Pediatr Hematol Oncol. 2015; 37(7):507-8 [PubMed] Related Publications
BACKGROUND: Inherited or acquired immune dysregulation is associated with increased risk of lymphoproliferative disorders (LPDs), including classic Hodgkin lymphoma (cHL). A germline mutation in interleukin-2-inducible T-cell kinase (ITK) is described in individuals manifesting B-cell LPDs, cHL, and hemophagocytic syndromes following Epstein-Barr virus (EBV) infection.
OBSERVATIONS: We report a novel ITK mutation in a child with EBV-associated cHL and multiple-site reactive polyclonal B-cell hyperplasia followed by relapsed cHL at another site. Following relapse, the child was successfully treated with allogeneic hematopoietic stem cell transplantation and EBV cytotoxic T cells.
CONCLUSIONS: ITK-mutated T cells cause a defective antiviral immune response and the resulting immune dysregulation can lead to EBV-associated polyclonal hyperplasia with subsequent outgrowth of neoplastic B-cell clones, which in some instances may progress to LPDs, including cHL.

Linabery AM, Erhardt EB, Richardson MR, et al.
Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children's Oncology Group study.
Int J Cancer. 2015; 137(9):2163-74 [PubMed] Free Access to Full Article Related Publications
Family history of lymphoid neoplasm (LN) is a strong and consistently observed Hodgkin lymphoma (HL) risk factor, although it has been only marginally examined in pediatric/adolescent patients. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL cases diagnosed at 0-14 years at Children's Oncology Group institutions in 1989-2003. Detailed histories were captured by structured telephone interviews with parents of 517 cases and 783 controls. Epstein-Barr virus (EBV) RNA detection was performed for 355 available case tumors. Two analytic strategies were applied to estimate associations between family cancer history and pediatric/adolescent HL. In a standard case-control approach, multivariate conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). In a reconstructed cohort approach, each relative was included as a separate observation, and multivariate proportional hazards regression was used to produce hazard ratios (HRs) and 95% CIs. Using the latter, pediatric/adolescent HL was associated with a positive family history (HR = 1.20, 95% CI: 1.06-1.36), particularly early-onset cancers (HR = 1.30, 95% CI: 1.06-1.59) and those in the paternal lineage (HR = 1.38, 95% CI: 1.16-1.65), with a suggested association for LN in first-degree relatives (HR = 3.61, 95% CI: 0.87-15.01). There were no discernable patterns for EBV+ versus EBV- HL. The clustering of LN within pedigrees may signal shared genetic susceptibility or common environmental exposures. Heritable genetic risk variants have only recently begun to be discovered, however. These results are consistent with other studies and provide a compelling rationale for family-based studies to garner information about genetic susceptibility to HL.

Alkhairy OK, Perez-Becker R, Driessen GJ, et al.
Novel mutations in TNFRSF7/CD27: Clinical, immunologic, and genetic characterization of human CD27 deficiency.
J Allergy Clin Immunol. 2015; 136(3):703-712.e10 [PubMed] Related Publications
BACKGROUND: The clinical and immunologic features of CD27 deficiency remain obscure because only a few patients have been identified to date.
OBJECTIVE: We sought to identify novel mutations in TNFRSF7/CD27 and to provide an overview of clinical, immunologic, and laboratory phenotypes in patients with CD27 deficiency.
METHODS: Review of the medical records and molecular, genetic, and flow cytometric analyses of the patients and family members were performed. Treatment outcomes of previously described patients were followed up.
RESULTS: In addition to the previously reported homozygous mutations c.G24A/p.W8X (n = 2) and c.G158A/p.C53Y (n = 8), 4 novel mutations were identified: homozygous missense c.G287A/p.C96Y (n = 4), homozygous missense c.C232T/p.R78W (n = 1), heterozygous nonsense c.C30A/p.C10X (n = 1), and compound heterozygous c.C319T/p.R107C-c.G24A/p.W8X (n = 1). EBV-associated lymphoproliferative disease/hemophagocytic lymphohistiocytosis, Hodgkin lymphoma, uveitis, and recurrent infections were the predominant clinical features. Expression of cell-surface and soluble CD27 was significantly reduced in patients and heterozygous family members. Immunoglobulin substitution therapy was administered in 5 of the newly diagnosed cases.
CONCLUSION: CD27 deficiency is potentially fatal and should be excluded in all cases of severe EBV infections to minimize diagnostic delay. Flow cytometric immunophenotyping offers a reliable initial test for CD27 deficiency. Determining the precise role of CD27 in immunity against EBV might provide a framework for new therapeutic concepts.

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] Free Access to Full Article 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.

Jones K, Wockner L, Thornton A, et al.
HLA class I associations with EBV+ post-transplant lymphoproliferative disorder.
Transpl Immunol. 2015; 32(2):126-30 [PubMed] Related Publications
Epstein-Barr virus (EBV) is frequently associated with post-transplant lymphoproliferative disorders (EBV(+) PTLD). In these cases, impaired Epstein-Barr virus (EBV)-specific CD8(+) T-cell immunity is strongly implicated and antigen presentation within the malignant B-cell is intact. Interestingly, several studies have reported HLA class I alleles with protective or susceptibility associations. However, results are conflicting, likely influenced by methodology including inconsistent use of multiple hypothesis testing. By contrast, HLA class I associations have been repeatedly reported for classical Hodgkin Lymphoma (cHL), in which EBV is also implicated in a proportion of cases. In contrast to EBV(+) PTLD which expresses the immunodominant EBV latency III EBNA3A/B/C proteins, EBV(+) cHL is restricted to the subdominant EBNA1/LMP1/LMP2 proteins. Herein, we report a study of HLA class I associations in EBV(+) PTLD, with 263 patients with lymphoma (cHL or PTLD) evaluated. Two Australian population cohorts, n = 23,736 and n = 891 were used for comparison. Contrary to previous reports, no HLA class I associations with EBV(+) PTLD were found, whereas for cHL known HLA class I associations were confirmed, with HLA-A*02 homozygous individuals having the lowest odds of developing EBV(+) cHL. Our results suggest that HLA class I does not influence susceptibility to the viral latency III expressing lymphoma, EBV(+) PTLD. Further studies are required for definitive confirmation.

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