Genome-Wide Association Study of Classical Hodgkin Lymphoma and Epstein–Barr Virus Status–Defined Subgroups

Urayama, Kevin Y.; Jarrett, Ruth F.; Hjalgrim, Henrik; Diepstra, Arjan; Kamatani, Yoichiro; Chabrier, Amélie; Gaborieau, Valérie; Boland, Anne; Nieters, Alexandra; Becker, Nikolaus; Foretová, Lenka; Benavente, Yolanda; Maynadié, Marc; Staines, Anthony; Shield, Lesley; Lake, Annette; Montgomery, Dorothy; Taylor, Malcolm; Smedby, Karin E.; Amini, Rose‐Marie; Adami, Hans‐Olov; Glimelius, Bengt; Feenstra, Bjarke; Nolte, Ilja M.; Visser, Lydia; Imhoff, Gustaaf W. van; Lightfoot, Tracy; Cocco, Pierluigi; Kiemeney, Lambertus A.; Vermeulen, Sita H.; Holcátová, Ivana; Vatten, Lars J.; Macfarlane, Gary J.; Thomson, Peter; Conway, David I.; Benhamou, Simone; Agudo, Antonio; Healy, Claire M.; Overvad, Kim; Tjønneland, Anne; Melin, Beatrice; Canzian, Federico; Khaw, Kay‐Tee; Travis, Ruth C.; Peeters, Petra H.M.; González, Carlos A.; Quiŕos, J. Ramón; Sánchez, María‐José; Huerta, José María; Ardanáz, Eva; Dorronsoro, Miren; Clavel‐Chapelon, Françoise; Bueno‐de‐Mesquita, H. Bas; Riboli, Elio; Roman, Eve; Boffetta, Paolo; Sanjosé, Sílvia de; Zélénika, Diana; Melbye, Mads; Berg, Anke van den; Lathrop, Mark; Brennan, Paul; McKay, James

doi:10.1093/jnci/djr516

Cited by 144 publications

(154 citation statements)

References 52 publications

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“…However, the impact of HLA class I on EBV latency antigen‐specific CD8 + T cell immunity has not been determined systematically. Interestingly, large epidemiological and genomewide association studies have consistently reported differential HLA class I susceptibility to EBV + cHL (Supporting information, Table S1) 14, 15, 16, 17. In western European populations, HLA‐A*01 and HLA‐B*37 are associated with increased susceptibility to EBV + cHL, while HLA‐A*02 is associated with protection 15, 16, 17.…”

Section: Introductionmentioning

confidence: 99%

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Jones

Wockner

Brennan

et al. 2015

Clinical and Experimental Immunology

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SummaryIn 40% of cases of classical Hodgkin lymphoma (cHL), Epstein–Barr virus (EBV) latency‐II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV+cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA‐A*02 is protective in EBV+cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA‐A*02– versus HLA‐A*02+ EBV+cHL patients, suggesting that LMP2A‐specific CD8+ T cell anti‐tumoral immunity may be relatively ineffective in HLA‐A*02– EBV+cHL. To ascertain the impact of HLA class I on EBV latency antigen‐specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV+cHL, the magnitude of ex‐vivo LMP1/2A‐specific CD8+ T cell responses was elevated in HLA‐A*02+ patients. Furthermore, in a controlled in‐vitro assay, LMP2A‐specific CD8+ T cells from healthy HLA‐A*02 heterozygotes expanded to a greater extent with HLA‐A*02‐restricted compared to non‐HLA‐A*02‐restricted cell lines. In an extensive analysis of HLA class I‐restricted immunity, immunodominant EBNA3A/3B/3C‐specific CD8+ T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A‐specific responses were confined largely to HLA‐A*02. Our results demonstrate that HLA‐A*02 mediates a modest, but none the less stronger, EBV‐specific CD8+ T cell response than non‐HLA‐A*02 alleles, an effect confined to EBV latency‐II antigens. Thus, the protective effect of HLA‐A*02 against EBV+cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency‐II antigen‐specific CD8+ T cell hierarchies.

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Section: Introductionmentioning

confidence: 99%

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Jones

Wockner

Brennan

et al. 2015

Clinical and Experimental Immunology

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“…Although T-cell and NK cell can also be infected by EBV, it mainly attacks B lymphocytes, thus the most common forms of EBVassociated lympho-proliferative disorders are B-cell lymphomas such as HL, Burkitt Lymphoma and diffuse large B-cell lymphoma (DLBCL) [24][25][26][27]. In nearly half of HL patients, the genome of EBV can be found [28][29][30]. Notably, EBV is more commonly associated with mixedcellularity HL and lymphocyte-depleted HL [28][29][30].…”

Section: Discussionmentioning

confidence: 99%

“…In nearly half of HL patients, the genome of EBV can be found [28][29][30]. Notably, EBV is more commonly associated with mixedcellularity HL and lymphocyte-depleted HL [28][29][30]. Therapeutic regimen for both EBV positive and negative cases of HL is currently identical, with long term remissions in most patients, but relapsed EBV positive HL patients have a poor prognosis [29,31].…”

Section: Discussionmentioning

confidence: 99%

Aggressive Natural Killer Cell Leukemia Secondary to Hodgkin Lymphoma: a Case Report and Review of the Literature

Xu¹,

Yang²,

Fu³

et al. 2015

Chemotherapy

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A 32-year old Chinese woman presented with high fever (39C), lymphadenopathy, hepatosplenomegaly, shortness of breath and general fatigue after initial remission of Hodgkin lymphoma (HL). The immuno-phenotype of blast cells found in her peripheral blood and pleural fluid suggested abnormal Natural Killer (NK) cells (CD2+CD3-CD56+CD45RO+HLADR+CD94+ with high Ki67). Her serum EB virus DNA was over 1.0×107IU/mL. Combining her clinical symptom and laboratory data, the patient was diagnosed with Hodgkin Lymphoma, secondary NK cell leukemia and haemophagocytic lymphohistocytosis (HLH). To date, this is the first reported case that developed secondary ANKL after the treatment of Hodgkin Lymphoma. Secondary treatment-related cancers are a major problem in HL survivors. Thus, novel treatment strategies for HL should aim at a reduction of chemotherapy and radiation therapy in order to reduce the risk for development of therapy-related malignancies. In conclusion, improvements of combined therapy as well as close monitoring during clinical follow up could warrant the improved overall survival of HL and prevent fatal complications.

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“…We re-examined five previously discovered single nucleotide polymorphisms (SNPs) of known associations to leukemia (rs7089424, rs10821936, rs10994982, rs4132601, and rs2239633), along with three HLA region susceptibility markers for lymphomas, since lymphoma and ALL both stem from lymphoid cells. These included rs2395185, a marker of HLA DRB4 lineage [23] which has previously shown associations with major leukemias including childhood ALL [24,25] and other diseases including Hodgkin lymphoma [26], lung cancer [27], rheumatoid arthritis [28], asthma [29], and ulcerative colitis [30][31][32]; rs10484561, which has been shown to be a strong risk marker in follicular lymphoma (FL) [33]; and rs2647012, which is a protective marker for FL [34]. These SNPs were examined in a multiethnic sample (non-Hispanic Whites, Hispanic Whites, and Blacks) from Houston, Texas to assess their association with ALL.…”

Section: Introductionmentioning

confidence: 99%

Genetic markers in a multi-ethnic sample for childhood acute lymphoblastic leukemia risk

Kennedy¹,

Kamdar²,

Lupo³

et al. 2014

Leukemia & Lymphoma

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Genome-wide association studies have identified multiple risk loci for childhood acute lymphoblastic leukemia (ALL), but mostly in European/White populations despite Hispanics having a greater risk. We re-examined SNPs of known associations with childhood ALL and known HLA region lymphoma risk markers in a multi-ethnic population. Significant associations were found in two ARID5B variants (rs7089424 and rs10821936). We replicated a strong risk association in non-Hispanic White males with rs2395185, a protective marker for lymphoma.Another HLA region marker, rs2647012, showed a risk association among Hispanics only, while a strong protective association was found with rs1048456, a follicular lymphoma risk marker.Our study validated this new case-control sample by confirming genetic markers associated with childhood ALL, and yielded new associations with lymphoma markers. Despite positive results, our study did not provide any clues to why Hispanics have a higher susceptibility to childhood leukemia, suggesting that environmental factors may have a strong contribution.

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Genome-Wide Association Study of Classical Hodgkin Lymphoma and Epstein–Barr Virus Status–Defined Subgroups

Abstract: Overall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.

Cited by 144 publications

References 52 publications

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Aggressive Natural Killer Cell Leukemia Secondary to Hodgkin Lymphoma: a Case Report and Review of the Literature

Genetic markers in a multi-ethnic sample for childhood acute lymphoblastic leukemia risk

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