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Polymorphisms of genes encoding cytokines predict the risk of high-grade bladder cancer and outcomes of BCG immunotherapy.

ABSTRACT: Introduction:The present study investigated the association of cytokines genes polymorphisms (IL-2, IL-8 and IL-18) and polymorphisms in genes encoding molecules related to the differentiation of Th17 subpopulation (IL-17 and IL-23R) with the risk of bladder cancer (BC) and response to BCG immunotherapy. Material and methods:Altogether, 175 BC patients treated with BCG due to high-grade non-muscle invasive tumors and 207 healthy individuals were genotyped for the following polymorphisms: IL-17A-197G>A (rs2275913); IL-17F+7488T>C (rs763780); IL-23Rc.309C>A (rs10889677);IL-23Rc.1142G>A (rs11209026); IL-2-330T>G (rs2069762), IL-8-251A>T (rs4073), and IL-18-137G>C (rs187238) using the TaqMan SNP genotyping assays. Results:The IL-23Rc.-309C>A[A] allele was associated with the risk of BC (OR: 1.42, p = 0.03). Moreover, heterozygocities for IL-17A-197G>A[GA] and IL-18-137G>C[GC] increased the risk of BC, as compared to both homozygotes (OR: 1.67, p = 0.01 and OR: 1.84, p = 0.008, respectively). The IL-18-137G>C[GC] heterozygous patients had the highest risk of tumor recurrence and progression, and the worst recurrence-free and progression-free survival. Homozygous IL-17A-197G>A[GG] patients presented the best recurrence-free survival, while IL-17A-197G>A[AA] patients had 1.8-fold higher risk of recurrence. Conclusions:The present study highlighted the importance of IL-17, IL-18, and IL-23R gene polymorphisms for BC susceptibility and BCG immunotherapy outcomes. It may help to identify appropriate candidates for early radical treatment.

SUBMITTER: Krajewski W

PROVIDER: S-EPMC7226548 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Polymorphisms of genes encoding cytokines predict the risk of high-grade bladder cancer and outcomes of BCG immunotherapy.

Krajewski Wojciech W Karabon Lidia L Partyka Anna A Tomkiewicz Anna A Poletajew Sławomir S Tukiendorf Andrzej A Kołodziej Anna A Zdrojowy Romuald R

Central-European journal of immunology 20200101 1

<h4>Introduction</h4>The present study investigated the association of cytokines genes polymorphisms (IL-2, IL-8 and IL-18) and polymorphisms in genes encoding molecules related to the differentiation of Th17 subpopulation (IL-17 and IL-23R) with the risk of bladder cancer (BC) and response to BCG immunotherapy.<h4>Material and methods</h4>Altogether, 175 BC patients treated with BCG due to high-grade non-muscle invasive tumors and 207 healthy individuals were genotyped for the following polymor ...[more]

PMID: 32425678

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Project description:PurposeBacillus Calmette-Guérin (BCG)-treatment is an established treatment for bladder cancer, but its mechanisms of action are not fully understood. High-risk non-muscle invasive bladder-cancer (NMIBC)-patients failing to respond to BCG-treatment have worse prognosis than those undergoing immediate radical cystectomy and identification of patients at risk for BCG-failure is of high priority. Several studies indicate a role for nitric oxide (NO) in the cytotoxic effect that BCG exerts on bladder cancer cells. In this study we investigated whether NO-synthase (NOS)-gene polymorphisms, NOS2-promoter microsatellite (CCTTT)n, and the NOS3-polymorphisms-786T>C (rs2070744) and Glu298Asp (rs1799983), can serve as possible molecular markers for outcome after BCG-treatment for NMIBC.Materials and methodsAll NMIBC-patients from a well-characterized population based cohort were analyzed (n=88). Polymorphism data were combined with information from 15-years of clinical follow-up. The effect of BCG-treatment on cancer-specific death (CSD), recurrence and progression in patients with varying NOS-genotypes were studied using Cox proportional hazard-models and log rank tests.ResultsBCG-treatment resulted in significantly better survival in patients without (Log rank: p=0.006; HR: 0.12, p=0.048), but not in patients with a long version ((CCTTT)n ≧13 repeats) of the NOS2-promoter microsatellite. The NOS3-rs2070744(TT) and rs1799983(GG)-genotypes showed decreased risk for CSD (Log rank(TT): p=0.001; Log rank(GG): p=0.010, HR(GG): 0.16, p=0.030) and progression (Log rank(TT): p<0.001, HR(TT): 0.05, p=0.005; Log rank(GG): p<0.001, HR(GG): 0.10, p=0.003) after BCG-therapy compared to the other genotypes. There was also a reduction in recurrence in BCG-treated patients that was mostly genotype independent. Analysis of combined genotypes identified a subgroup of 30% of the BCG-treated patients that did not benefit from BCG-treatment.ConclusionsOur results suggest that the investigated polymorphisms influence patient response to BCG-treatment and thus may serve as possible markers for identification of BCG-failures.

Project description:IntroductionInflammatory response during sepsis is incompletely understood due to small sample sizes and variable timing of measurements following the onset of symptoms. The vasopressin in septic shock trial (VASST) compared the addition of vasopressin to norepinephrine alone in patients with septic shock. During this study plasma was collected and 39 cytokines measured in a 363 patients at both baseline (before treatment) and 24 hours. Clinical features relating to both underlying health and the acute organ dysfunction induced by the severe infection were collected during the first 28 days of admission.HypothesisCluster analysis of cytokines identifies subgroups of patients at differing risk of death and organ failure.MethodsCirculating cytokines and other signaling molecules were measured using a Luminex multi-bead analyte detection system. Hierarchical clustering was performed on plasma values to create patient subgroups. Enrichment analysis identified clinical outcomes significantly different according to these chemically defined patient subgroups. Logistic regression was performed to assess the importance of cytokines for predicting patient subgroups.ResultsPlasma levels at baseline produced three subgroups of patients, while 24 hour levels produced two subgroups. Using baseline cytokine data, one subgroup of 47 patients showed a high level of enrichment for severe septic shock, coagulopathy, renal failure, and risk of death. Using data at 24 hours, a larger subgroup of 81 patients that largely encompassed the 47 baseline subgroup patients had a similar enrichment profile. Measurement of two cytokines, IL2 and CSF2 and their product were sufficient to classify patients into these subgroups that defined clinical risks.ConclusionsA distinct pattern of cytokine levels measured early in the course of sepsis predicts disease outcome. Subpopulations of patients have differing clinical outcomes that can be predicted accurately from small numbers of cytokines. Design of clinical trials and interventions may benefit from consideration of cytokine levels.

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Polymorphisms of genes encoding cytokines predict the risk of high-grade bladder cancer and outcomes of BCG immunotherapy.

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Polymorphisms of genes encoding cytokines predict the risk of high-grade bladder cancer and outcomes of BCG immunotherapy.

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