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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:PURPOSE:Bacillus 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 METHODS:All 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. RESULTS:BCG-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. CONCLUSIONS:Our 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.

Project description:Both lncRNAs and the N6-methyladenosine (m6A) modification are key regulators of tumorigenesis and innate immunity. However, little is known about the m6A modification of lncRNAs and their clinical and immune relevance in bladder cancer. In this study, we identified m6A-related lncRNAs using Pearson correlation analysis in The Cancer Genome Atlas (TCGA) and the IMvigor210 datasets. Next, univariate Cox regression was performed using the TCGA dataset to filter prognostic m6A-related lncRNAs, which were further subjected to the least absolute shrinkage and selection operator (LASSO) Cox regression to establish a 12 m6A-related lncRNA prognostic score (m6A-LRS). The m6A-LRS was validated in the IMvigor210 dataset. In addition, high m6A-LRS tumors, characterized by decreased tumor mutation load and neoantigen load, showed poorer response to immunotherapy than those with low m6A-LRS in the IMvigor210 dataset. Further, we constructed an m6A-LRS-based nomogram that demonstrated a strong ability to predict overall survival in patients with bladder cancer. Moreover, enrichment analysis revealed that tumor-associated biological processes, oncogenic signaling, and tumor hallmarks were commonly associated with a high m6A-LRS. Gene set variation analysis also indicated that high m6A-LRS was associated with activation of canonical oncogenic signatures, such as the epithelial-to-mesenchymal transition, cell cycle regulators, and DNA replication, as well as activation of immunosuppressive signatures, such as the T-cell exhaustion and pan-fibroblast-TGF-β response signatures. Furthermore, we observed distinct tumor microenvironment cell infiltration characteristics between high- and low-risk tumors. High m6A-LRS tumors showed reduced infiltration of CD8+ T-cells and enhanced infiltration of macrophages and fibroblasts. Additionally, we established a competing endogenous RNA network based on the12 m6A-related lncRNAs. Finally, three lncRNAs (SNHG16, SBF2-AS1, and BDNF-AS) were selected for further validation. The qualitative PCR assay on 10 pairs of bladder cancer and adjacent normal control samples validated the differential expression, and methylated RNA immunoprecipitation (MeRIP) analysis demonstrated a robust m6A enrichment in T24 bladder cancer cells compared with normal uroepithelial cells (SVHUC-1). In conclusion, this study introduced an m6A-related lncRNA signature that identified a subgroup of patients with poor prognoses and suboptimal immune responses, thus providing novel approaches for treatment response prediction and patient stratification in bladder cancer.

Project description:Bacillus Calmette-Guerin (BCG) is a live attenuated form of Mycobacterium bovis that was developed 100 years ago as a vaccine against tuberculosis (TB) and has been used ever since to vaccinate children globally. It has also been used as the first-line treatment in patients with nonmuscle invasive bladder cancer (NMIBC), through repeated intravesical applications. Numerous studies have shown that BCG induces off-target immune effects in various pathologies. Accumulating data argue for the critical role of the immune system in the course of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we tested whether repeated exposure to BCG during the treatment of NMIBC is associated with the risk of developing AD and PD. We presented a multi-center retrospective cohort study with patient data collected between 2000 and 2019 that included 12,185 bladder cancer (BC) patients, of which 2301 BCG-treated patients met all inclusion criteria, with a follow-up of 3.5 to 7 years. We considered the diagnosis date of AD and nonvascular dementia cases for BC patients. The BC patients were partitioned into those who underwent a transurethral resection of the bladder tumor followed by BCG therapy, and a disjoint group that had not received such treatment. By applying Cox proportional hazards (PH) regression and competing for risk analyses, we found that BCG treatment was associated with a significantly reduced risk of developing AD, especially in the population aged 75 years or older. The older population (≥75 years, 1578 BCG treated, and 5147 controls) showed a hazard ratio (HR) of 0.726 (95% CI: 0.529-0.996; p-value = 0.0473). While in a hospital-based cohort, BCG treatment resulted in an HR of 0.416 (95% CI: 0.203-0.853; p-value = 0.017), indicating a 58% lower risk of developing AD. The risk of developing PD showed the same trend with a 28% reduction in BCG-treated patients, while no BCG beneficial effect was observed for other age-related events such as Type 2 diabetes (T2D) and stroke. We attributed BCG's beneficial effect on neurodegenerative diseases to a possible activation of long-term nonspecific immune effects. We proposed a prospective study in elderly people for testing intradermic BCG inoculation as a potential protective agent against AD and PD.

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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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