Association with HLA class I in Epstein-Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin's lymphoma

Diepstra, Arjan; Niens, Marijke; Vellenga, Edo; Imhoff, van Gustaaf; Nolte, Ilja M.; Schaapveld, Michael; Steege, Gerrit van der; Berg, van den Anke; Kibbelaar, RE; Meerman, te Gerhardus; Poppema, Sibrand

doi:10.1016/s0140-6736(05)66780-3

Cited by 151 publications

(153 citation statements)

References 24 publications

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“…No association was observed between the subject groups and the control HLA class III marker D6S273. These findings are similar to recent reports associating the HLA class I region, in particular the D6S510 (284-bp allele) and D6S265 (126-bp allele) microsatellite markers, with EBV-positive HL (19,20) and provide further evidence for an etiological link between IM and EBV-positive HL.…”

Section: Discussionsupporting

confidence: 92%

“…DNA was extracted from PBMCs using the Easy DNA Extraction Kit (Invitrogen) per the manufacturer's instructions and stored at -20°C until required. Three microsatellite markers, 2 from the HLA class I (D6S265 and D6S510) and 1 from the HLA class III regions (D6S273), were amplified using PCR performed in a total volume of 10 μl containing 25 ng of DNA (19). The reaction mix contained 1× GoTaq Flexi buffer (pH 8.5), 2.5 mM magnesium chloride, 200 μM dNTP (GE Healthcare), 25 μM of forward and reverse primer, and 0.5 units of GoTaq Flexi polymerase (Promega).…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies have highlighted HLA class I associations with both EBV-positive HL and NPC. Diepstra et al identified alleles of 2 microsatellite markers (D6S265: 126-bp allele; and D6S510: 284-bp allele) that are significantly associated with EBV-positive HL and a class III microsatellite, D6S273, that correlated with EBV-negative HL (19). Further work by the same group found SNPs within an 80-kb region, located near the HLA-A and HcG9 genes, which are also associated with EBV-positive HL (20).…”

Section: Introductionmentioning

confidence: 99%

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HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection

McAulay

Higgins²,

Macsween³

et al. 2007

J. Clin. Invest.

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Infectious mononucleosis (IM) is an immunopathological disease caused by EBV that occurs in young adultsand is a risk factor for Hodgkin lymphoma (HL). An association between EBV-positive HL and genetic markers in the HLA class I locus has been identified, indicating that genetic differences in the HLA class I locus may alter disease phenotypes associated with EBV infection. To further determine whether HLA class I alleles may affect development of EBV-associated diseases, we analyzed 2 microsatellite markers and 2 SNPs located near the HLA class I locus in patients with acute IM and in asymptomatic EBV-seropositive and -seronegative individuals. Alleles of both microsatellite markers were significantly associated with development of IM. Specific alleles of the 2 SNPs were also significantly more frequent in patients with IM than in EBV-seronegative individuals. IM patients possessing the associated microsatellite allele had fewer lymphocytes and increased neutrophils relative to IM patients lacking the allele. These patients also displayed higher EBV titers and milder IM symptoms. The results of this study indicate that HLA class I polymorphisms may predispose patients to development of IM upon primary EBV infection, suggesting that genetic variation in T cell responses can influence the nature of primary EBV infection and the level of viral persistence.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection

McAulay

Higgins²,

Macsween³

et al. 2007

J. Clin. Invest.

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“…The human leukocyte antigen (HLA) genes, located within the MHC region, have been implicated in the etiology of cHL (7)(8)(9)(10)(11). Some associations show heterogeneity by tumor EBV status (9,(11)(12)(13)(14) reinforcing the importance of acknowledging EBV status in examining the etiology of cHL.…”

Section: Introductionmentioning

confidence: 99%

A Novel Risk Locus at 6p21.3 for Epstein–Barr Virus-Positive Hodgkin Lymphoma

Delahaye-Sourdeix

Urayama

Gaborieau

et al. 2015

Cancer Epidemiology, Biomarkers &Amp; Prevention

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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 ¼ 7 Â 10

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“…The human leukocyte antigen (HLA) region on chromosome 6 has been associated with HL in several studies. [10][11][12] Other non-HLA susceptibility loci have been identified through GWAS. [13][14][15] The identification of genes with major susceptibility effects has been more difficult.…”

mentioning

confidence: 99%

Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene

et al. 2016

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H odgkin lymphoma shows strong familial aggregation but no major susceptibility genes have been identified to date. The goal of this study was to identify high-penetrance variants using whole exome sequencing in 17 Hodgkin lymphoma prone families with three or more affected cases or obligate carriers (69 individuals), followed by targeted sequencing in an additional 48 smaller HL families (80 individuals). Alignment and variant calling were performed using standard methods. Dominantly segregating, rare, coding or potentially functional variants were further prioritized based on predicted deleteriousness, conservation, and potential importance in lymphoid malignancy pathways. We selected 23 genes for targeted sequencing. Only the p.A1065T variant in KDR (kinase insert domain receptor) also known as VEGFR2 (vascular endothelial growth factor receptor 2) was replicated in two independent Hodgkin lymphoma families. KDR is a type III receptor tyrosine kinase, the main mediator of vascular endothelial growth factor induced proliferation, survival, and migration. Its activity is associated with several diseases including lymphoma. Functional experiments have shown that p.A1065T, located in the activation loop, can promote constitutive autophosphorylation on tyrosine in the absence of vascular endothelial growth factor and that the kinase activity was abrogated after exposure to kinase inhibitors. A few other promising mutations were identified but appear to be "private". In conclusion, in the largest sequenced cohort of Hodgkin lymphoma families to date, we identified a causal mutation in the KDR gene. While independent validation is needed, this mutation may increase downstream tumor cell proliferation activity and might be a candidate for targeted therapy.

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Association with HLA class I in Epstein-Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin's lymphoma

Cited by 151 publications

References 24 publications

HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection

HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection

A Novel Risk Locus at 6p21.3 for Epstein–Barr Virus-Positive Hodgkin Lymphoma

Whole exome sequencing in families at high risk for Hodgkin lymphoma: identification of a predisposing mutation in the KDR gene

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