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

Background Associations of Hodgkin's lymphoma with HLA have been reported for many years. In 20-40% of patients with this disorder, Epstein-Barr virus (EBV) is present in the neoplastic cells. Because presentation of EBV antigenic peptides can elicit vigorous immune responses, we investigated associations of the HLA region with EBV-positive and EBV-negative Hodgkin's lymphoma.

Methods In a retrospective, population-based study, patients with Hodgkin's lymphoma were reclassified according to the WHO classification, and EBV status was assessed by in-situ hybridisation of EBV-encoded small RNAs. Germline DNA was isolated from 200 patients diagnosed between 1987 and 2000 and from their first-degree relatives. Genotyping was done with 33 microsatellite markers spanning the entire HLA region and two single-nucleotide polymorphisms in the genes for tumour necrosis factor alpha and beta. Classic association analysis and the haplotype sharing statistic were used to compare patients with controls.

Findings Classic association analysis (but not the haplotype sharing statistic) showed an association of consecutive markers D6S265 and D6S510 (p=0.0002 and 0.0003), located in the HLA class I region, with EBV-positive lymphomas. The haplotype sharing statistic (but not classic association analysis) showed a significant difference in mean haplotype sharing between patients and controls surrounding marker D6S273 (p=0.00003), located in HLA class III.

Interpretation Areas within the HLA class I and class III regions are associated with susceptibility to Hodgkin's lymphoma, the association with class I being specific for EBV-positive disease. This finding strongly suggests that antigenic presentation of EBV-derived peptides is involved in the pathogenesis of EBV-involved Hodgkin's lymphoma.

Relevance to practice Polymorphisms in the HLA region could explain ethnic variation in the incidence of Hodgkin's lymphoma. The association of EBV-positive Hodgkin's lymphoma with HLA class I suggests that this polymorphism might affect the proper presentation of EBV antigens to cytotoxic T lymphocytes.