GENETIC POLYMORPHISMS IN THE TUMOR-NECROSIS-FACTOR LOCUS INFLUENCE NON-HODGKINS-LYMPHOMA OUTCOME

Systemic release of tumor necrosis factor (TNF) and lymphotoxin-alpha (LT alpha) has been found to contribute to the severity of non-Hodgkin 's lymphoma (NHL), We investigated whether genetic polymorphisms in th e INF locus, previously shown to influence TNF and LT alpha genes expr ession, might contribute to these cytokines production and to the clin ical course of NHL. Genomic DNA from 273 lymphoma patients was typed f or TNF (-308) polymorphism using an allele-specific polymerase chain r eaction (PCR) and for LT alpha (+252) polymorphism with a PCR-based re striction fragment length polymorphism. The presence of the TNF allele involved in increased TNF gene transcription was associated with high er plasma levels of this cytokine at the time of lymphoma diagnosis (c hi(2) test, P = .013). An extended haplotype analysis showed that the presence of at least two TNF or LT alpha high-producer alleles constit uted a risk factor for first-line treatment failure (chi(2) test, P = .021), shorter progression-free survival (log-rank test, P = .0007), a nd overall survival (log-rank test, P = .012). In the subgroup of 126 patients with diffuse large-cell lymphoma, the presence of two or more TNF/LT alpha high producing alleles contributed significantly to a hi gher rate of relapse and progression (log-rank test, P = .045 and P = .027). In multivariate Cox regression models including the variables o f the International Prognostic Index, the TNF/LT alpha haplotype statu s was found to be an independent risk factor for progression-free surv ival (relative risk 2.33, 95% confidence interval [1.17 to 4.64], P = .0053) and overall survival (relative risk 1.92, 95% confidence interv al [0.63 to 5.80], P = .081) of large-cell lymphoma patients. These re sults indicate that genetic polymorphism leading to increased TNF prod uction influences the outcome of NHL and suggest a pathophysiological role for the genetic control of the immune response in lymphoid malign ancies. (C) 1998 by The American Society of Hematology.