Human leukocyte antigens and genetic susceptibility to lymphoma

Tissue Antigens. 2015 Aug;86(2):98-113. doi: 10.1111/tan.12604.


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 and HLA variation suggest that antigen presentation, or lack of, plays an important role in disease pathogenesis but the precise mechanisms have yet to be elucidated.

Keywords: B-cell lymphoma; Epstein-Barr virus; Hodgkin lymphoma; human leukocyte antigen.

Publication types

  • Review

MeSH terms

  • Alleles
  • Epstein-Barr Virus Infections / complications
  • Epstein-Barr Virus Infections / genetics*
  • Epstein-Barr Virus Infections / immunology
  • Epstein-Barr Virus Infections / pathology
  • Gene Expression
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Haplotypes
  • Herpesvirus 4, Human / pathogenicity
  • Herpesvirus 4, Human / physiology
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class I / immunology
  • Histocompatibility Antigens Class II / genetics*
  • Histocompatibility Antigens Class II / immunology
  • Hodgkin Disease / complications
  • Hodgkin Disease / genetics*
  • Hodgkin Disease / immunology
  • Hodgkin Disease / pathology
  • Humans
  • Lymphoma, Non-Hodgkin / complications
  • Lymphoma, Non-Hodgkin / genetics*
  • Lymphoma, Non-Hodgkin / immunology
  • Lymphoma, Non-Hodgkin / pathology
  • Polymorphism, Single Nucleotide


  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II