Genetic polymorphisms in the the human leukocyte antigens (HLA DRB) loci and non-Hodgkin's lymphoma outcome.

E Kalinkaa, P Juszczynski a, G Sallesc, G Woszczekb, M Borowiecb, E Lech-Marandaa, L Baseggioc, M Kowalskib, T Robaka, B Coiffierc, K Warzochaa.

aDepartment of Hematology and bDepartment of Clinical Immunology, Medical University of Lodz, Poland; and cService d'Hematologie, Centre Hospitalier Lyon-Sud, Pierre Benite, France

AIM: The association between the tumor necrosis factor (TNF) promoter polymorphisms and non-Hodgkin's lymphoma (NHL) outcome was found to be related to the TNF-308 allele. As it's located at 1 Mb telomeric of HLA-DR, we considered the possibility that this association might be related to HLA class II antigens. METHODS: HLA DRB alleles were typed in 204 patients with NHL and 120 unrelated healthy controls by the membrane-bound sequence-specific labeled oligonucleotide probes. RESULTS: HLA DRB1*03 allele was associated with TNF-308A (p<.0001), yet none of the HLA DRB alleles were associated with susceptibility to nor with NHL prognostic variables. HLA DRB1*02 although not linked with the TNF -308A allele remained the only HLA DRB allele strongly associated with freedom from progression (FFP) (p=.006) but not with overall survival (OS) (p=.137). Indeed, the absence of the HLA DRB1*02 allele in individuals possessing the TNF (-308A) allele contributed to a shorter FFP (p=.004) and OS (p=.005). These referred to diffuse large B-cell (DLBCL) (p=0.003 and p=.005, FFP and OS respectively) rather than to follicular (FL) NHL (p=0.758 and p=.607, FFP and OS respectively). The logistic regression analysis to investigate the TNF-308 and HLA DRB1*02 alleles together with histology (DLBCL and FL) and prognostic variables of the International Prognostic Index identified HLA DRB1*02 as an independent determinant of FFP and OS, especially in DLBCL. CONCLUSIONS: Innate immunity reflected by the allelic polymorphisms within HLA DRB1 and/or some other linked alleles within the MHC region contributes to NHL outcome, especially of DLBCL type. The previously reported association with the TNF-308A allele remained unchanged, suggesting there are at least two independent genetic effects contributing to this phenomenon.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prognostic Markers.