The aim of the study was to investigate whether interleukin-10 (IL-10) genetic polymorphisms influence this cytokine production as well as the incidence and outcome of diffuse large B-cell lymphoma (DLBCL). The frequency of IL-10 -1082G allele was found to be higher in 199 patients with DLBCL as compared with 112 control subjects (0.47 versus 0.39, P ‫؍‬ .043). Increased serum levels of IL-10 were associated with adverse prognostic factors and poor DLBCL outcome. The frequencies of IL-10 -819T and IL-10 -592A alleles were lower in patients with elevated IL-10 serum levels (0.155 versus 0.32, P ‫؍‬ .14).

Systemic release of tumor necrosis factor (TNF) and lymphotoxin-α (LTα) has been found to contribute to the severity of non-Hodgkin's lymphoma (NHL). We investigated whether genetic polymorphisms in the TNF locus, previously shown to influence TNF and LTα genes expression, might contribute to these cytokines production and to the clinical course of NHL. Genomic DNA from 273 lymphoma patients was typed for TNF (−308) polymorphism using an allele-specific polymerase chain reaction (PCR) and for LTα (+252) polymorphism with a PCR-based restriction fragment length polymorphism. The presence of the TNF allele involved in increased TNF gene transcription was associated with higher plasma levels of this cytokine at the time of lymphoma diagnosis (χ2 test, P = .013). An extended haplotype analysis showed that the presence of at least two TNF or LTα high-producer alleles constituted a risk factor for first-line treatment failure (χ2 test, P = .021), shorter progression-free survival (log-rank test, P = .0007), and 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/LTα high producing alleles contributed significantly to a higher rate of relapse and progression (log-rank test, P = .045 and P = .027). In multivariate Cox regression models including the variables of the International Prognostic Index, the TNF/LTα haplotype status was found to be an independent risk factor for progression-free survival (relative risk 2.33, 95% confidence interval [1.17 to 4.64], P = .0053) and overall survival (relative risk 1.92, 95% confidence interval [0.63 to 5.80],P = .081) of large-cell lymphoma patients. These results indicate that genetic polymorphism leading to increased TNF production influences the outcome of NHL and suggest a pathophysiological role for the genetic control of the immune response in lymphoid malignancies.

It has been recently shown that DNA methyl transferase overexpression is correlated with unfavourable prognosis in human malignancies while methylation deregulation remains a hallmark that defines acute myeloid leukemia (AML). The oncogenic transcription factor EVI1 is involved in methylation deregulation and its overexpression plays a major role for predicting an adverse outcome. Moreover, the identification of DNMT3A mutations in AML patients has recently been described as a poor prognostic indicator. In order to clarify relationship between these key actors in methylation mechanisms and their potential impact on patient outcomes, we analysed 195 de novo AML patients for the expression of DNMT3A, 3B (and its non-catalytic variant 3BNC) and their correlations with the outcome and the expression of other common prognostic genetic biomarkers (EVI1, NPM1, FLT3ITD/TKD and MLL) in adult AML. The overexpression of DNMT3B/3BNC is (i) significantly correlated with a shorter overall survival, and (ii) inversely significantly correlated with event-free survival and DNMT3A expression level. Moreover, multivariate analysis showed that a high expression level of DNMT3B/3BNC is statistically a significant independent poor prognostic indicator. This study represents the first report showing that the overexpression of DNMT3B/3BNC is an independent predictor of poor survival in AML. Its quantification should be implemented to the genetic profile used to stratify patients for therapeutical strategies and should be useful to identify patients who may benefit from therapy based on demethylating agents.