Genetic polymorphisms of STAT3 correlated with prognosis in diffuse large B-cell lymphoma patients treated with rituximab.
ABSTRACT: BACKGROUND:Rituximab in the combination of CHOP chemotherapy has been widely used as the standard treatment for several kinds of B-cell non-Hodgkin lymphoma (B-NHL). Inactivation of phosphorylation of STAT3 plays an essential role in rituximab-induced anti-proliferative activity in B-cell lymphoma. However, the relationship between STAT3 genetic polymorphisms and clinical response to standard frontline treatment with rituximab has not been well illustrated yet. METHODS:In this study we analyzed the STAT3 polymorphisms and prognosis of 166 diffuse large B-cell lymphoma (DLBCL) patients who were treated with rituximab from 2007 to 2010. Determination of the STAT3 polymorphisms of rs2293152 from genomic DNA was achieved by Sanger chain termination sequencing. RESULTS:We did not observe obvious correlation between patients' disease features and STAT3 polymorphisms, but patients with homozygous genotypes at rs2293162 showed a trend of higher CR rate than those with the heterozygous genotype, especially in non-GCB subgroup (p?=?0.011). Furthermore, homozygous genotypes GG and CC also showed advantages of long-term survival compared with heterozygous genotype patients (p?=?0.022). CONCLUSIONS:These results suggest that STAT3 polymorphisms could be a suitable biomarker related to clinical outcome of DLBCL patients treated with rituximab.
Project description:BACKGROUND: The precise mechanism of action for rituximab (R) is not fully elucidated. Besides antibody-dependent cellular cytotoxicity (ADCC), complements may also play an important role in the clinical response to rituximab-based therapy in diffuse large B cell lymphoma (DLBCL). The purpose of this study was to explore the relationship between C1qA polymorphism and the clinical response to standard frontline treatment with R-CHOP in DLBCL patients. METHODS: Genotyping for C1qA[276A/G] was done in 164 patients with DLBCL. 129 patients treated with R-CHOP as frontline therapy (R ≥ 4 cycles) were assessable for the efficacy. RESULTS: Patients with homozygous A were found to have a higher overall response rate than those with heterozygous or homozygous G alleles (97.3% vs. 83.7%,P = 0.068). The complete response rate in patients with homozygous A was statistically higher than that in AG and GG allele carriers (89.2% vs. 51.1%,P = 0.0001). The overall survival of patients with homozygous A was longer than that of the G allele carriers (676 days vs. 497 days, P = 0.023). Multivariate Cox regression analysis showed that C1qA A/A allele was an independent favorable prognostic factor for DLBCL patients treated with R-CHOP as first-line therapy. CONCLUSION: These results suggest that C1qA polymorphism may be a biomarker to predict response to R-CHOP as frontline therapy for DLBCL patients.
Project description:Treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has greatly improved clinical outcomes in patients with diffuse large B-cell lymphoma (DLBCL) compared with CHOP. The mechanism of rituximab-induced cell death is poorly understood. We found that rituximab does not enhance the directly killing efficacy of CHOP, as tested on a panel of DLBCL cell lines. Rituximab induced a rapid release of HMGB1 (High mobility group protein B 1). This release is independent of cell death but significantly correlated with an inhibition on STAT3 activity. In the resting state, HMGB1 co-localizes and interacts with STAT3 in the nucleus of DLBCL cells. Treatment with rituximab breaks this binding and triggers HMGB1 release. Treatment with R-CHOP but not CHOP significantly increased plasma HMGB1 and decreased IL-10 concentrations in DLBCL patients compared with controls. The conditioned medium from rituximab-treated DLBCL cells is able to trigger dendritic cell maturation, phagocytosis, and IFN-? secretion by cytotoxic T cells. In conclusion, our results demonstrate that rituximab induces an inhibition on STAT3 activity, leading to increased HMGB1 release and decreased IL-10 secretion, which elicits immune responses, suggesting that indirect effects on the immune system rather than direct killing contribute to elimination of DLBCL.
Project description:OBJECTIVE: An association between susceptibility to inflammatory bowel disease (IBD) and polymorphisms of both the tyrosine kinase 2 gene (TYK2) and the signal transducer and activator of transcription 3 gene (STAT3) was examined in a Japanese population in order to identify the genetic determinants of IBD. METHODS: The study subjects comprised 112 patients with ulcerative colitis, 83 patients with Crohn's disease (CD), and 200 healthy control subjects. Seven tag single-nucleotide polymorphisms (SNPs) in TYK2 and STAT3 were detected by PCR-restriction fragment length polymorphism. RESULTS: The frequencies of a C allele and its homozygous C/C genotype at rs2293152 SNP in STAT3 in CD patients were significantly higher than those in control subjects (P = 0.007 and P = 0.001, respectively). Furthermore, out of four haplotypes composed of the two tag SNPs (rs280519 and rs2304256) in TYK2, the frequencies of a Hap 1 haplotype and its homozygous Hap 1/Hap1 diplotype were significantly higher in CD patients in comparison to those in control subjects (P = 0.023 and P = 0.024, respectively). In addition, the presence of both the C/C genotype at rs2293152 SNP in STAT3 and the Hap 1/Hap 1 diplotype of TYK2 independently contributes to the pathogenesis of CD and significantly increases the odds ratio to 7.486 for CD (P = 0.0008). CONCLUSION: TYK2 and STAT3 are genetic determinants of CD in the Japanese population. This combination polymorphism may be useful as a new genetic biomarker for the identification of high-risk individuals susceptible to CD.
Project description:We evaluated the impact of functional polymorphisms in the vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor 2 (VEGFR2) genes on the survival of patients with diffuse large B cell lymphoma (DLBCL). Five potentially functional polymorphisms in the VEGFA (rs699947, rs2010963 and rs3025039) and VEGFR2 (rs1870377 and rs2305948) genes were assessed in 494 DLBCL patients treated with rituximab plus CHOP chemotherapy. The associations of genotype and haplotype with overall survival (OS) and progression-free survival (PFS) were analyzed. Of the five polymorphisms, VEGFR2 rs1870377T>A was significantly associated with both OS and PFS; in the dominant model, patients with the AA + TA genotypes had significantly better OS (P = 0.002) and PFS (P = 0.004) than those with the TT genotype. The association between significantly better OS and the AA + TA genotypes was observed separately in patients with low (0-2; P = 0.035) and high (3-5; P = 0.043) International Prognostic Index scores. Multivariate analysis showed that, relative to the AA + TA genotypes, the TT genotype was an independent prognostic factor for poor OS (HR, 1.71; 95% CI, 1.21-2.43; P = 0.002) and PFS (HR, 1.57; 1.13-2.17; P = 0.004). Other independent significant predictors of survival in patients with DLBCL were International Prognostic Index score, age > 60 years, lactate dehydrogenase concentration >normal, extranodal disease >1 and presence of B symptoms. The VEGFR2 rs1870377 polymorphism might affect survival in patients with DLBCL, suggesting that angiogenesis might be related to poor survival in these patients.
Project description:The impact of pharmacogenetics on predicting survival in diffuse large B-cell lymphoma (DLBCL) remains unclear. We tested 337 DLBCL patients treated with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for 9 single nucleotide polymorphisms from 6 genes (CD20, FCGR2A, NAD(P)H, ABCC2, ABCG2 and CYP3A5). Patients who carried the NCF4 rs1883112 GG genotype showed significantly shorter progression-free survival (PFS) (P = 0.023) and event-free survival (EFS) (P < 0.001) comparing with A allele. A significantly shortened PFS (P = 0.013) and EFS (P = 0.002) was also observed in the patients with ABCG2 rs2231137 GG genotype. Furthermore, the elder (> 60 years old) or male patients with ABCG2 rs2231137 GG genotype had poorer PFS and EFS than A allele. Moreover, CD20 rs2070770 CC and RAC2 rs13058338 AT genotypes were independent predictors of chemotherapy-induced toxicity. Cox proportional hazards analyses demonstrated that the GG genotype of ABCG2 rs2231137 and NCF4 rs1883112 were risk factors in DLBCL patients. In conclusion, the identified polymorphisms provide guide for the identification of DLBCL patients who are likely to benefit from chemotherapy.
Project description:The aim of this study was to explore the association between polymorphisms in signal transducer and activator of transcription protein 3 (STAT3) and the risk of gastric cancer. In the present study, a case-control study was conducted in which rs2293152 and rs744166 polymorphisms in STAT3 were analyzed in 209 Chinese patients with gastric cancer and 294 cancer-free controls. The genotypes were determined by polymerase chain reaction restriction fragment length polymorphism method. For the rs744166 polymorphism, the TC genotype (adjusted OR = 0.60, 95% CI = 0.39-0.92, and P = 0.020) and CC genotype (adjusted OR = 0.41, 95% CI = 0.21-0.80, and P = 0.009) were associated with a decreased risk of gastric cancer compared to the TT genotype. However, rs2293152 did not show any difference in gastric cancer risk between patients and controls in the CG/CC genotype compared to the GG genotype. Besides, the SNP effects were additive to the effects of environmental factors without any interaction between them in the susceptibility to gastric cancer. Collectively, rs744166 polymorphism might be significantly associated with a decreased risk of gastric cancer in a Chinese population. Additionally, polymorphisms in STAT3, along with environmental factors, might be associated with the development of gastric cancer.
Project description:The influence of Fc gamma receptor IIIA (FCGR3A) 158V/F polymorphisms on the response to rituximab (R) plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone; R-CHOP) therapy in diffuse large B-cell lymphoma (DLBCL) is uncertain. Thus, a retrospective study and a meta-analysis were performed to examine the possible correlation between FCGR3A 158V/F polymorphism and the response rate of R-CHOP regimen in patients with newly diagnosed DLBCL. The genotypes of FCGR3A 158V/F in 164 newly diagnosed DLBCL patients treated with R-CHOP were determined in this retrospective study. Additionally, a meta-analysis of current and previously published studies was conducted. Overall response rate (complete and partial response, ORR) and complete response rate (CR) were evaluated. The results of our retrospective study showed lack of correlation between FCGR3A 158V/F polymorphism and ORR (p=0.78) or CR (p=0.76) with R-CHOP therapy. A meta-analysis of 731 cases also showed lack of significant association of ORR and CR in all genetic models with FCGR3A 158V/F polymorphism. In survival analysis, the homozygous F genotype correlated with a shorter progression-free survival than that of non-F/F genotype (p=0.05), this was significant for the non-GC subset of DLBCL (p=0.04), but no association was found between overall survival and FCGR3A 158V/F polymorphism. Further analysis with nonsuperiority test (p<0.0001) suggested that FCGR3A 158V/F polymorphism was not associated with better ORR or CR in newly diagnosed DLBCL patient treated with R-CHOP. No clear relationship was found between FCGR3A 158V/F polymorphism and response to frontline R-CHOP therapy in patients with DLBCL.
Project description:BACKGROUND:R-CHOP has significantly improved survival rates of patients with diffuse large B cell lymphoma (DLBCL) by ~20% as compared to CHOP. CD20 antigen, highly expressed on more than 80% of B-cell lymphomas, is the target for rituximab. The goal of our study was to examine polymorphism in the CD20 gene in Chinese DLBCL population and whether CD20 gene polymorphism is associated with clinical response to R-CHOP. METHOD:CD20 gene polymorphism was detected in the entire coding regions including 6 exons by polymerase chain reaction (PCR)-sequencing assay in 164 patients with DLBCL. Among them, 129 patients treated with R-CHOP as frontline therapy (R???4 cycles) were assessable for the efficacy. RESULTS:Polymorphisms at three single nucleotides (SNP) were identified in the entire coding regions of the CD20 gene in the 164 patients. One of them, CD20 Exon2  was found to be highly correlated with response to R-CHOP. Patients with homozygous C genotype showed a trend toward higher overall response rate than others with CT plus TT genotype (90.6% vs. 79.5%; P =0.166). A trend toward higher complete remission (CR) rate was observed in patients with homozygous C genotype (67.4%) compared with CT plus TT genotype (47.1%) (P?=?0.091). CONCLUSION:These results suggest that there are 3 SNPs in CDS of the CD20 gene in Chinese DLBCL population. The CC genotype at Exon2  appears to be associated with favourable response to R-CHOP.
Project description:OBJECTIVE:p53 gene, as "the guardian of the genome", is the most widely studied tumor suppressor gene. Previous studies have shown that about 50 percent of tumors have P53 dysfunction. This article aims to retrospectively analyze the correlation between p53 rs1625895 polymorphism and the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). METHODS:PCR combined with Sanger sequencing were used to detect rs1625895 genotype in 384 DLBCL patients. The relationship between rs1625895 polymorphisms and the clinical characteristics, first-line therapeutic effects and the prognosis of the patients were analyzed. RESULTS:Among all the patients, 2 (0.5%) patients with AA genotype, 34 (8.9%) patients with AG genotype and 348 (90.6%) patients with GG genotype were identified. The patients with different rs1625895 genotypes did not have any difference in terms of age, gender, B symptoms (developing any of the following symptoms: unexplained recurrent fever (often above 38 °C), night sweats, and unexplained weight loss of 10% within 6 months ), erythrocyte sedimentation rate (ESR), international prognostic index (IPI) and molecular subtype (P>0.05). The overall response rate (ORR) was 82.9% and 82.8% in AA/AG and GG, respectively. There was no significant dif?ference between the first-line therapeutic effects of the two groups (P>0.05). And there was also no difference between A allele carriers and homozygous G allele carriers for the 5-year progression?free survival rate (PFS) (71.8% vs. 62.3%, ?2=1.351, P=0.245) and 5-year overall survival rate (OS) (72.2% vs. 64.1%, ?2=1.267, P=0.260). But in the subgroup with Germinal Center B-cell (GCB) type, the patients carrying A allele for rs1625895 had an obviously longer PFS (91.7% vs. 72.7%, ?2=4.493, P=0.034) and OS (91.7% vs. 76.7%, ?2=4.246, P=0.039) compared with the patients homozygous for the G allele. As for the patients with non-GCB subtype, there was no significant difference in PFS and OS between different rs1625895 genotypes (P>0.05). According to whether the first-line regimen contained rituximab or not, the patients were divided into two groups treated with cyclophosphoramide, doxorubicin, vincristine and prednisone (CHOP) or with rituximab and CHOP (R-CHOP). But in both subgroups, there was no significant difference in the 5-year PFS and OS between the AA/AG and GG patients, too (P>0.05). CONCLUSION:For DLBCL patients receiving CHOP regimen chemotherapy in the first line, p53 rs1625895 cannot predict the clinical efficacy and prognosis of the patients, but in the patients with GCB subtype, this polymorphism may be a prognostic indicator.
Project description:Rheumatoid arthritis (RA) is the most common systemic inflammatory disease and is of unknown etiology. The altered balance between immunosuppressive and inflammatory T cell subpopulations exerts a huge impact on RA pathogenesis. The STAT3 protein regulates genes involved in the immune responses. It regulates maturation of T and B cells. Its abnormal activity is significantly associated with autoimmune diseases and cancer development. We aimed to evaluate the contribution of three potentially functional single nucleotide polymorphisms (SNPs) within the STAT3 gene to susceptibility and severity of RA in the Polish population.A total of 595 patients with RA and 330 healthy individuals were included in the study. DNA from patients and healthy subjects was obtained from peripheral blood using standard DNA isolating methods. The STAT3 rs1053005, rs1026916 and rs2293152 polymorphisms were genotyped using the TaqMan SNP genotyping assay. The accuracy of SNP genotyping was confirmed using direct DNA sequence analysis.The distribution of STAT3 polymorphisms did not differ significantly between cases and controls. Our results revealed a tendency only, where rs1026916 AA genotype occurred more frequently in RA patients compared to healthy controls, in codominant (p = 0.09), dominant (p = 0.06) and recessive (p = 0.09) models. STAT3 rs2293152 polymorphism was associated with higher DAS28 (p = 0.014 codominant model; p = 0.003 dominant model), increased number of swollen joints (p = 0.02), higher VAS (p = 0.01) and higher HAQ score (p = 0.05).We did not observe a significant association between the three studied STAT3 genetic variants and increased susceptibility to or severity of RA. Only the STAT3 rs2293152 polymorphism was associated with parameters that indicate a more severe course of the disease. However, its distribution did not differ between RA and control groups. According to our observations these 3 studied STAT3 SNPs may not be used as risk factors for developing RA.