HLA specificities are related to development and prognosis of diffuse large B-cell lymphoma

Abstract

Key Points• DLBCL patients carrying the HLA-B44 supertype have a worse progression-free and overall survival after R-CHOP-like treatment.• The HLA-DRB1*01 allele increases the risk of DLBCL development.Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n 5 64, 26%) or with (n 5 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs 19.5%, P 5 .0008, Pc 5 .0104) and a lower frequency of HLA-C*03 (6.4% vs 17.9%, P < .0005, Pc 5 .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P 5 .019) and 5-year overall (71% vs 92%, P 5 .001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect. (Blood. 2013;122(8):1448-1454 IntroductionSeveral genetic polymorphisms have been associated with susceptibility or prognosis in various B-cell non-Hodgkin lymphoma (B-NHL) subtypes.1,2 In recent years, genome-wide association studies have identified 6p21.3 as a risk region for susceptibility of different lymphomas, such as follicular lymphoma [3][4][5] or Hodgkin lymphoma. 6,7 The HLA system, located in this region, plays a key role in antitumor immune responses and lymphoma-cell apoptosis 8 and so may be essential for neoplasia control. Previous studies have shown a relationship between HLA polymorphisms and susceptibility to certain hematologic malignancies such as chronic lymphocytic leukemia, multiple myeloma, and acute lymphoblastic leukemia.9-11 However, there is little information about the relationship between HLA polymorphisms and susceptibility to developing B-NHL or their outcomes.12-16 Focusing on diffuse large B-cell lymphoma (DLBCL), some associations between HLA specificities and this B-NHL subtype have been described, as well as with other genetic polymorphisms. Shorter progression-free survival (PFS) and overall survival (OS) have been observed in DLBCL patients lacking the HLA-DR2 or carrying TNF -308A.13 In addition, OS is shorter in those patients carrying the C*07-B*08-LTA1 252G -TNF -308A haplotype 14 or the HLA-C*07:01. 16 However, these studies considered patients treated before...

HLA superfamily assignment is a predictor of immune response to cancer testis antigens and survival in ovarian cancer

“…On the other hand, HLA-B44 has been associated with worse prognosis, both PFS and OS, in patients with diffuse large B-cell lymphoma [18]. In the present study HLA-B44 was also associated with worse progression-free and overall survival.…”

“…Therefore, it is possible that the immunogenicity of NY-ESO-1 is largely affected by patients’ HLA types. HLA type has previously been implicated in the risk for and outcomes of patients with HIV, viral hepatitis, tuberculosis, and other cancers [15–18]. It has also been associated with certain autoimmune diseases, such as ankylosing spondylitis, autoimmune hepatitis, type I diabetes, and autoimmune polyendocrine syndrome [19–21].…”

The role of HLA variation in lymphoma aetiology and survival

“…In an analysis of HLA class I alleles in 154 NHL patients, HLA‐B*08 and HLA‐A*01 alleles were also identified with poor NHL prognosis . Additional associations include decreased 5‐year progression‐free survival and 5‐year overall survival with HLA‐B*44 and HLA‐B*18 in a single‐centre study in Spain of 250 DLBCL patients . Non‐HLA SNPs in the HLA region have also been implicated, including inferior OS with the TAP2 (rs241447) SNP in a study of 216 DLBCL patients .…”

HLA polymorphism and risk of multiple myeloma

“…The HLA associations observed here and in GWAS demonstrate that the HLA region is a key risk locus for mature B-cell malignancies(15, 16). MM etiology often involves clonal immunoglobulin production directed against post-translationally modified human proteins, such as hyperphosphorylated paratarg-7 (P-7) or sumoylated Hsp90(17, 18).…”