Genetic polymorphisms in the tumor necrosis factor (TNF) gene promoter influence non-Hodgkin's lymphoma outcome.

P Juszczynskia, E Kalinka 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: To investigate the influence of genetic polymorphisms within TNF promoter on clinical course of non-Hodgkin's lymphomas (NHL). METHODS: DNA samples from 204 patients with NHL were PCR-amplified and sequenced between nucleotides -675 to -143 of the TNF promoter. RESULTS: No polymorphisms other than -376, -308, and -238 of the TNF promoter were found. Their frequencies were similar in NHL patients and Caucasian healthy controls. There was a higher frequency of the TNF-308A in diffuse large B-cell (DLBCL) than in follicular (FL) NHL (p=.0548). Its frequency was higher in patients with elevated TNF plasma levels (p=.0155) and in those who didn't achieve complete response (CR) (p=.0093). TNF-308A was associated with shorter freedom from progression (FFP) and overall survival (OS) (p=.008 and p=017, respectively), which referred to DLBCL (p=0.037 and p=.033, respectively) rather than to FL subgroup (p=0.708 and p=.790, respectively). TNF-376 and -238 alleles' frequencies were similar in DLBCL/FL subgroups. However, only the TNF-308A remained associated with elevated plasma levels of the TNF, refractory disease, and shorter FFP and OS. CONCLUSIONS: Innate immunity reflected by genetic predisposition of the host to regulate TNF production contributes to the clinical course of NHL, especially DLBCL subtype. The association between the TNF promoter polymorphisms and NHL outcome seemed to be related to the TNF-308 allele and could not be explained by the TNF-376, -238, -163 alleles.

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