Human leukocyte antigen and classical Hodgkin lymphoma

Classical Hodgkin lymphoma (cHL) is a complex cancer, the incidence and its association with Epstein-Barr virus (EBV) varies significantly with age, sex, histological subtype, ethnicity, geography and socio-economic status. CHL is characterized by minority tumor cells in a large background of reactive immune cells, showing strong involvement of immune system. Both genome wide and targeted gene association studies show strong association of human leukocyte antigen (HLA) with cHL susceptibility, however, mostly lacking cHL subgroup analysis stratified based on age, EBV and subtype. In this thesis, we systematically reviewed genetic polymorphisms in the cHL and concluded that HLA region is strongly associated with cHL susceptibility. Several non-HLA gene associations are found to be important for the immunopathology of the disease. Genetic associations for cHL prognosis and secondary malignancies and toxicities are limited. Next, we determined the associations between classical HLA class I and class II alleles and susceptibility to cHL overall and specific cHL subgroups stratified based on age and tumor cell EBV status. HLA class I alleles are associated with EBV+ cHL and HLA class II alleles with EBV- cHL susceptibility. The alleles of the HLA-DQB1*06-DRB1*15 haplotype are associated with risk of cHL at younger age (≤45 years), whereas the alleles of the HLA-B*08-DRB1*03 haplotype are risk factors for cHL at older age (>45 years. In a Brazilian cHL population showed that HLA-A*01 is a risk allele and HLA-A*02 is a protective allele for developing EBV+ cHL. This susceptibility pattern is similar to the pattern observed in the Western Europe population.The findings of this thesis support the relevance of HLA alleles in susceptibility of cHL. The observed HLA associations in cHL are consistent with the proposed immunological nature of the disease and the importance of the infiltrating T cells. The findings contribute to a better understanding of the susceptibility mechanisms in cHL.

Dissertation: http://irs.ub.rug.nl/ppn/387521267