Genetic variations in tumor necrosis factor (TNF) and interleukin-10 (IL-10) were reported to influence susceptibility to and outcome of patients with non-Hodgkin lymphoma. Therefore, we investigated whether single nucleotide polymorphisms in TNF and IL-10 may play a role in the clinical course of patients with chronic lymphocytic leukemia (CLL). TNF-308G>A, IL-10-3575T>A, and IL-10-1082A>G seem to be functionally relevant, were genotyped in 292 previously untreated patients with CLL. The control group consisted of 192 randomly selected blood donors. The patients carrying TNF-308GG and IL-10-1082AA genotypes presented a higher 3-year treatment-free survival (56.6 vs. 40.6%, P = 0.05) as well as a 10-year overall survival (OS) rates (92.3 vs. 57.6%, P = 0.005) than those with other TNF-308 and IL-10-1082 genotype combinations. Multivariate analysis demonstrated the Rai stage (P = 0.0002), IGHV mutation status (P = 0.01), TNF-308G>A (P = 0.03), and TNF/IL-10 polymorphism-based risk groups (P = 0.05) to be independent factors predicting OS. When the mutated IGHV patients were analyzed, the homozygotes TNF-308GG and IL-10-1082AA presented a higher 10-year OS rate than those carrying other TNF-308 and IL-10-1082 genotypes (100 vs. 67.7%, P = 0.01). In the unmutated IGHV patients, only the TNF-308G>A polymorphism influenced OS. The genetic variations in TNF and IL-10 genes work as independent predictors of survival and may play a role in the clinical course of CLL. It suggests inherited ability of the host to shift the balance between the Th1 and Th2 response, which in turn might contribute to the pathogenesis and prognosis of B-cell malignancies.

Tumor necrosis factor (TNF)-α and interleukin (IL)-10 are cytokines involved in the balance between cell-mediated and humoral immunity. We investigated whether serum TNF-α and IL-10 levels have any impact on clinical outcome of patients with chronic lymphocytic leukemia (CLL). TNF-α and IL-10 levels were determined in the serum of 160 CLL patients at the time of diagnosis. The cytokine low-risk group consisted of patients with either TNF-α and IL-10 levels below their medians or those with only one elevated parameter. Both TNF-α and IL-10 levels greater than or equal to their medians defined the cytokine high-risk group. The high-risk patients presented a shorter 3-year treatment-free survival (TFS) than low-risk subjects (15 vs. 69.6 %; p < 0.0001). The high-risk group (p = 0.0002) along with high leukocyte count (p < 0.0001) and unmutated immunoglobulin heavy-chain variable region genes (p < 0.0001) independently predict the risk of progression in patients with Rai stage 0-II. Furthermore, the high-risk group had an independent prognostic impact on shorter TFS both in patients with mutated (24.3 vs. 78.2 %; p < 0.0001) and unmutated (8.2 vs. 49 %; p = 0.004) immunoglobulin heavy-chain variable region genes (IGHV) as compared to the low-risk group. The estimated 5-year overall survival (OS) of high-risk patients was shorter than those in the low-risk group (83.3 vs. 97.1 %; p = 0.003). Multivariate analysis demonstrated the cytokine high-risk group (p = 0.02) followed by Rai stage III-IV (p = 0.048) to be independent factors predicting shorter OS. At diagnosis, TNF-α and IL-10 may predict the outcome of patients with CLL.

The role of HLA-G is extensively studied in cancer due to its inhibition of the immune response. Several polymorphisms in the HLA-G gene have been reported to significantly affect its expression. We, therefore, investigated whether functionally relevant HLA-G polymorphisms, HLA-G-725C/G/T, and HLA-G 14-base pair, have any influence on the susceptibility to diffuse large B-cell lymphoma (DLBCL) and its clinical course. The polymorphisms were genotyped in 207 previously untreated patients with DLBCL and 150 unrelated controls. A significant difference in genotype distribution of HLA-G polymorphic genotypes between the patients and controls was found. The frequencies of the HLA-G-725GG or the HLA-G-725GC genotype were lower, and those of the HLA-G ins/ins genotype were higher in the patients compared with the controls. Patients carrying the HLA-G-725CC genotype presented a higher probability of overall survival (OS) than subjects with other genotype combinations of HLA-G-725C/G/T (P = 0.003). The homozygous HLA-G del/del had a lower probability of OS than subjects carrying the HLA-G deletion/insertion (del/ins) or the HLA-G ins/ins genotype (P = 0.009). Two HLA-G genotype-based risk groups were defined according to the genotype distribution. The high-risk (HR) group presented a shorter OS than low-risk (LR) patients (P = 0.001). In a multivariate analysis adjusted for International Prognostic Index (IPI) factors, both the intermediate high/high IPI-risk group (P < 0.0001) and the HR genotype group (P = 0.004) independently increased the risk of death. This is the first study indicating an important role of HLA-G polymorphisms for the clinical course of DLBCL. The potential influence of HLA-G polymorphisms on the susceptibilityto DLBCL thus deserves further study.

There is growing evidence that genetic variations in the human leukocyte antigen (HLA) genes play a role in the etiology and clinical course of NHL. HLA-G belongs to the non-classical class I major histocompatibility complex-1 (MHC-I) polymorphic molecules and due to its suppression of immune response it is able to facilitate tumor escape from immunosurveillance. Several polymorphisms in the HLA-G gene have been reported to significantly affect its expression. Therefore, we investigated whether functionally relevant HLA-G polymorphisms, HLA-G-725C/G/T and HLA-G 14-bp, have any influence on the susceptibility to, and clinical course of, diffuse large B-cell lymphoma (DLBCL). The polymorphisms were genotyped in 207 previously untreated patients with DLBCL and 150 unrelated controls. A significant difference in genotype distribution of HLA-G polymorphic genotypes between the patients and controls was found. The frequencies of the HLA-G-725GG or the HLA-G-725GC genotype were lower (OR [odds ratio]= 0.47, P= 0.004), and those of the HLA-G ins/ins genotype were higher (OR= 2.08, P= 0.004) in the patients compared to controls. In univariate logistic regression analysis, neither HLA-G -725C/G/T nor HLA-G 14-bp influenced the probability of achieving a remission. There was no influence of HLA-G polymorphisms on the probability of progression-free survival (PFS). However, the patients carrying the HLA-G-725CC genotype presented a higher probability of 5-year overall survival (OS) than subjects with other genotype combinations of HLA-G-725C/G/T (38.2% vs 21.7%, P=0.003, log-rank test). The estimated 5-year OS among the homozygotes HLA-G del/del was 18.9% compared to the 35.3% in the subjects carrying the HLA-G del/ins or the 46.1% in those with the HLA-G ins/ins genotype (P=0.009, log-rank test). In a multivariate Cox analysis adjusted for IPI factors, we found that both the HLA-G -725C/G/T polymorphism (P= 0.01) and the IPI (P< 0.0001) retained their independent prognostic impact on OS The influence of the particular genotypes of the HLA-G -725C/G/T and the HLA-G 14-bp polymorphism on OS allow us to single out two HLA-G genotype-based risk groups. The low risk (LR) group included the patients carrying the HLA-G -725CC genotype and the HLA-G del/ins or the HLA-G ins/ins genotype. In contrast, the high risk (HR) group comprised those patients with other HLA-G genotype combinations. It is worth noting that the estimated 5-year OS rate of patients with LR genotypes was 42.7% in comparison to the 19.3% (P= 0.001, log-rank test) in patients with HR genotypes. An additional multivariate analysis, including HLA-G genotype-based risk groups and the IPI, revealed that both the intermediate high/high IPI risk group (P< 0.0001) and the HR genotype group (P= 0.004) independently increased the risk of death. This is the first study indicating an important role for HLA-G polymorphisms in the clinical course of DLBCL. The potential influence of HLA-G polymorphisms on the susceptibility to DLBCL deserves further study. It would seem that the inherited ability of the host to suppress anti-tumor immune response and then facilitate tumor escape from immunosurveillance might contribute to the pathogenesis and prognosis of B-cell malignancies. Disclosures Robak: MorphoSys AG: Research Funding.

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