Abstract
The pathogenesis of classical Hodgkin lymphoma (cHL) involves environmental and genetic factors. To explore the role of the human leukocyte antigen (HLA) genes, we performed a case-control genotyping study in 338 Dutch cHL patients using a PCR-based sequence-specific oligonucleotide probe (SSOP) hybridization approach. The allele frequencies were compared to HLA typings of more than 6,000 controls. The age of the cHL patients varied between 13 and 81 years with a median of 35 years. Nodular sclerosis subtype was the most common subtype (87%) and EBV was detected in 25% of the cHL patients. HLA-B5 was significantly increased and HLA-DR7 significantly decreased in the total cHL patient population as compared to controls. Two class II associations were observed to be specific for the EBV− cHL population with an increase of HLA-DR2 and HLA-DR5. Allele frequencies of HLA-A1, HLA-B37 and HLA-DR10 were significantly increased in the EBV+ cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in Caucasians. The allele frequency of HLA-A2 was significantly decreased in the EBV+ cHL population. Analysis of haplotypes with a frequency of >1% revealed a significant increase of HLA-A2-B7-DR2 in EBV− cHL as compared to controls. SSOP association analysis revealed significant differences between EBV+ and EBV− cHL patients for 19 probes that discriminate between HLA-A*01 and HLA-A*02. In conclusion, the HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV+ cHL. Furthermore several new protective and predisposing HLA class I and II associations for the EBV+, the EBV− and the entire cHL population were identified.
Highlights
Classical Hodgkin lymphoma is a typical multi-factorial disease with both environmental and genetic factors acting together to cause disease [1,2]
Age at time of diagnosis was similar in the Epstein Barr virus (EBV)+ and EBV2 group, i.e. 37 in EBV+ and 32 in EBV2. 43 of 338 Classical Hodgkin lymphoma (cHL) patients could not be subtyped and were designated cHL not otherwise specified (NOS)
A number of Human Leukocyte Antigen (HLA) genes, alleles and serotypes have previously been reported to be involved in the pathogenesis of cHL [5,6,7] and genome wide association studies (GWAS) indicated the most significant associations for cHL to be within the HLA locus [18,19]
Summary
Classical Hodgkin lymphoma (cHL) is a typical multi-factorial disease with both environmental and genetic factors acting together to cause disease [1,2]. Genetic associations with specific Human Leukocyte Antigen (HLA) alleles have been reported in both sporadic and familial cHL [5,6,7]. The expression pattern of EBV genes in Hodgkin Reed-Sternberg (HRS) cells is restricted to the two latent membrane proteins (LMP1 and LMP2) and the EBV nuclear antigen 1 (EBNA1) [8]. Despite the lack of immunodominant EBV proteins, LMP and EBNA1-specific T cell responses can be efficiently induced in the context of specific HLA class I or class II molecules [9,10,11]. The extreme diversity of HLA genes influences both the affinity and specificity of antigenic peptide binding and is responsible for variations in host anti-viral immune defenses. Genetic variation in host anti-viral immune responses related to HLA polymorphisms might be an important contributor to the development of virally induced malignancies
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