HLA Associations in Classical Hodgkin Lymphoma: EBV Status Matters

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.

Genetic Associations in Classical Hodgkin Lymphoma: A Systematic Review and Insights into Susceptibility Mechanisms

“…In addition, several other HLA class II SNPs are associated with cHL (15,45 Ã 07:01 allele (45). This is in line with HLA typing studies that showed that HLA-DRB1 Ã 07:01 is a protective allele for developing NS cHL (26,29,30). Two SNPs mapping to nonclassical HLA genes in the HLA region, that is, MHC class I polypeptiderelated sequence B (MICB) (6p21.33) and proline-rich transmembrane protein 1 (PRRT1) (6p21.32) are associated with cHL overall, NS cHL, or EBV À cHL (15,45,47).…”

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

“…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.…”

Infectious, autoimmune and allergic diseases and risk of Hodgkin lymphoma in children and adolescents: A Children's Oncology Group study

“…2,3 Rheumatoid arthritis has been consistently associated with HL in adults, conferring an estimated 3.3-fold greater risk, 15 while associations between other autoimmune diseases and HL have been observed in adults as well. 16,17 In addition, genome-wide association 18 and other genetic studies 19 have identified variants in HLA genes linked to increased HL susceptibility.…”

“…4,18,19 To our knowledge, no prior studies have examined risk by tumor EBV status in pediatric and adolescent HL, although the available data indicate such stratification is warranted.…”