Human leukocyte antigens and genetic susceptibility to lymphoma

Familial aggregation, coupled with ethnic variation in incidence, suggests that inherited susceptibility plays a role in the development of lymphoma, and the search for genetic risk factors has highlighted the contribution of the human leukocyte antigen ( HLA) complex. In a landmark study published almost 50 years ago, Hodgkin lymphoma ( HL) was the first disease to be associated with HLA variation. It is now clear that Epstein- Barr virus ( EBV)- positive and - negative HL are strongly associated with specific HLA polymorphisms but these differ by EBV status of the tumours. HLA class I alleles are consistently associated with EBV- positive HL while a polymorphism in HLA class II is the strongest predictor of risk of EBV- negative HL. Recent investigations, particularly genome- wide association studies ( GWAS), have also revealed associations between HLA and common types of non- Hodgkin lymphoma ( NHL). Follicular lymphoma is strongly associated with two distinct haplotypes in HLA class II whereas diffuse large B- cell lymphoma is most strongly associated with HLA- B* 08. Although chronic lymphocytic leukaemia is associated with variation in HLA class II, the strongest signals in GWAS are from non- HLA polymorphisms, suggesting that inherited susceptibility is explained by co- inheritance of multiple low risk variants. Associations between B- cell derived lymphoma andHLAvariation suggest that antigen presentation, or lack of, plays an important role in disease pathogenesis but the precise mechanisms have yet to be elucidated.