scholarly journals ASSESSMENT OF A PROGNOSTIC VALUE OF CDKN2A AND TIMP3 GENE METHYLATION IN BLADDER CANCER

Author(s):  
M. P. Smal ◽  
N. V. Nikitchenko ◽  
A. I. Rolevich ◽  
T. I. Nabebina ◽  
S. A. Krasny ◽  
...  

Promoter hypermethylation of tumor suppressor genes is one of the mechanisms of epigenetic regulation disturbance of gene expression and is often observed in different cancer types. The profile of mutational and epigenetic changes characterizes a malignant potential of a tumor, as well as its ability to invade and metastasize.The aim of the study was to determine a prognostic value of p16, p14ARF and TIMP3 gene methylation in the group of 158 bladder cancer patients. Epigenetic changes in these genes were observed with a frequency of 11.4, 0 and 10.8 %, respectively, and did not depend on clinic-morphological characteristics.A statistically significant association of p16 and TIMP3 abnormal methylation with smoking was found, indicating a possible influence of tobacco smoke carcinogens on the occurrence of these epigenetic changes. In the multivariate Cox regression analysis, p16 promoter hypermethylation was an independent predictor for bladder cancer progression (HR 6.84; 95 % CI 1.6–29.9; р = 0.011).The use of the data on the p16 methylation status may improve the accuracy of prognosis of the bladder cancer clinical course and the selection of appropriate treatment strategy.

Author(s):  
M. P. Smal ◽  
N. V. Nikitchenko ◽  
A. I. Rolevich ◽  
T. I. Nabebina ◽  
S. A. Krasny ◽  
...  

To accurately predict the tumor behavior and individualize the treatment approach, new methods for bladder cancer (BC) prognosis are required. The most promising prognostic markers are the mutational and epigenetic changes of genes involved in maintaining cellular homeostasis. In the present study, we evaluated the influence of p16 promoter hypermethylation on the risk of recurrence, progression and disease outcome in the group of 158 BC patients. p16 epigenetic changes were found in 11.4 % of urothelial carcinomas and did not depend on clinicоmorphological characteristics. However, in the subgroup of patients with non-muscle invasive tumors, p16 abnormal methylation was significantly associated with smoking, and in the subgroup of patients with muscle-invasive BC, it was linked to a high tumor grade (G3). In the multivariate Cox regression analysis, p16 promoter hypermethylation was an independent predictor for bladder cancer progression (HR 6.84; 95 % CI 1.6–29.9; р = 0.011). The use of the data on the p16 methylation status may improve the accuracy of prognosis of the bladder cancer clinical course and the selection of appropriate treatment strategy.


2021 ◽  
Vol 1 (3) ◽  
pp. 77-87
Author(s):  
Gong Xiao ◽  
Qiongjing Yuan ◽  
Wei Wang

Background: Multiple myeloma (MM) is one of the most common cancers of the blood system. N6-methyladenosine (m6A) plays an important role in cancer progression. We aimed to investigate the prognostic relevance of the m6A score in multiple myeloma through a series of bioinformatics analyses. Methods: The microarray dataset GSE4581 and GSE57317 used in this study were downloaded from the Gene Expression Omnibus (GEO) database. The m6A score was calculated using the GSVA package. The Random forests, univariate Cox regression analysis and Lasso analyses were performed for the differentially expressed genes (DEGs). Kaplan–Meier analysis and an ROC curve were used to diagnose the effectiveness of the model. Results: The GSVA R software package was used to predict the function. A total of 21 m6A genes were obtained, and 286 DEGs were identified between high and low m6A score groups. The risk model was constructed and composed of PRX, LBR, RB1, FBXL19-AS1, ARSK, MFAP3L, SLC44A3, UNC119 and SHCBP1. Functional analysis of risk score showed that with the increase in the risk score, Activated CD4 T cells, Memory B cells and Type 2 T helper cells were highly infiltrated. Conclusions: Immune checkpoints such as HMGB1, TGFB1, CXCL9 and HAVCR2 were significantly positively correlated with the risk score. We believe that the m6A score has a certain prognostic value in multiple myeloma.


2015 ◽  
Vol 2015 ◽  
pp. 1-6 ◽  
Author(s):  
Young-Won Kim ◽  
Hyung-Yoon Yoon ◽  
Sung Pil Seo ◽  
Sang Keun Lee ◽  
Ho Won Kang ◽  
...  

DNA methylation is the most common and well-characterized epigenetic change in human cancer. Recently, an association betweenprostate cancer susceptibility candidate(PRAC) methylation and genitourinary cancer was proposed. The aim of the present study was to evaluate the association betweenPRACmethylation status and clinicopathological parameters and prognosis in long-term follow-up primary nonmuscle invasive bladder cancer (NMIBC). The clinical relevance ofPRACmethylation was determined in 136 human bladder specimens (eight normal controls [NCs] and 128 primary NMIBCs) using quantitative pyrosequencing analysis.PRACmethylation was significantly higher in NMIBC patients than in NCs and was significantly associated with higher grade and more advanced stage of cancer. Kaplan-Meier estimates revealed significant difference in tumor recurrence and progression according toPRACmethylation status (bothp< 0.05). Multivariate Cox regression analysis revealed that thePRACmethylation status was a strong predictor of recurrence (hazard ratio [HR], 2.652;p= 0.012) and progression (HR, 9.531;p= 0.035) of NMIBC. Enhanced methylation status ofPRACwas positively associated with a high rate of recurrence and progression in NMIBC patients, suggesting thatPRACmethylation may be a promising prognostic marker of NMIBC.


2009 ◽  
Vol 31 (6) ◽  
pp. 487-500
Author(s):  
Gayatri Sharma ◽  
Sameer Mirza ◽  
Yi-Hsin Yang ◽  
Rajinder Parshad ◽  
Priya Hazrah ◽  
...  

Background: Methylation-mediated suppression of detoxification, DNA repair and tumor suppressor genes has been implicated in cancer development. This study was designed to investigate the impact of concurrent methylation of multiple genes in breast tumors on disease prognosis.Methods: Methylation specific PCR was carried out to analyze the methylation status of seven genes in archived breast tissues and determine the effect of aberrant methylation of multiple genes on disease prognosis and patients’ survival.Results: Promoter hypermethylation was observed in PRB 67%, ERα 64%, RASSF1A 63%, p16INK4A 51%, PRBβ2 22%, GSTP1 25% and BRCA1 27% of the breast cancers, respectively. Concurrent methylation of BRCA1, ERα, GSTP1 and RARβ2, was observed in a large proportion of breast cancers analyzed, suggesting that these genes do not appear to be methylated alone. Patients with high methylation indices had poor prognosis (p < 0.001, Hazards ratio = 14.58). Cox regression analysis showed RARβ2 promoter methylation to be an independent important determinant of breast cancer prognosis.Conclusions: Our results suggest that methylation of multiple genes plays an important role in prognosis of breast cancer. Our study not only describes the association of methylation mediated silencing of multiple genes with the severity of disease, but also drives to speculate the molecular crosstalk between genes or genetic pathways regulated by them individually.


2021 ◽  
Vol 8 ◽  
Author(s):  
Kezhen Yi ◽  
JingChong Liu ◽  
Yuan Rong ◽  
Cheng Wang ◽  
Xuan Tang ◽  
...  

Background: Every year, nearly 170,000 people die from bladder cancer worldwide. A major problem after transurethral resection of bladder tumor is that 40–80% of the tumors recur. Ferroptosis is a type of regulatory necrosis mediated by iron-catalyzed, excessive oxidation of polyunsaturated fatty acids. Increasing the sensitivity of tumor cells to ferroptosis is a potential treatment option for cancer. Establishing a diagnostic and prognostic model based on ferroptosis-related genes may provide guidance for the precise treatment of bladder cancer.Methods: We downloaded mRNA data in Bladder Cancer from The Cancer Genome Atlas and analyzed differentially expressed genes based on and extract ferroptosis-related genes. We identified relevant pathways and annotate the functions of ferroptosis-related DEGs using Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis and Gene Ontology functions. On the website of Search Tool for Retrieving Interacting Genes database (STRING), we downloaded the protein-protein interactions of DEGs, which were drawn by the Cytoscape software. Then the Cox regression analysis were performed so that the prognostic value of ferroptosis-related genes and survival time are combined to identify survival- and ferroptosis-related genes and establish a prognostic formula. Survival analysis and receiver operating characteristic curvevalidation were then performed. Risk curves and nomograms were generated for both groups to predict survival. Finally, RT-qPCR was applied to analyze gene expression.Results: Eight ferroptosis-related genes with prognostic value (ISCU, NFE2L2, MAFG, ZEB1, VDAC2, TXNIP, SCD, and JDP2) were identified. With clinical data, we established a prognostic model to provide promising diagnostic and prognostic information of bladder cancer based on the eight ferroptosis-related genes. RT-qPCR revealed the genes that were differentially expressed between normal and cancer tissues.Conclusion: This study found that the ferroptosis-related genes is associated with bladder cancer, which may serve as new target for the treatment of bladder cancer.


2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi143-vi143
Author(s):  
Toru Umehara ◽  
Hideyuki Arita ◽  
Ema Yoshioka ◽  
Tomoko Shofuda ◽  
Manabu Kinoshita ◽  
...  

Abstract INTRODUCTION Recent studies have reported that NFKBIA deletion (dNFKBIA) was potentially associated with worse prognosis in glioblastoma (GBM) patients. However, no consensus has been reached to its universal prognostic value. Here, we investigated the survival impact of dNFKBIA using two primary IDH wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). Additionally, prognostic impact of a combination of NFKBIA copy number and MGMT methylation status was evaluated. METHOD The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The survival impact of dNFKBIA and/or unmethylated MGMT (uMGMT) were analyzed for 212 KNBTG cases and 265 TCGA cases. The hazard ratio (HR) and p-value were computed using Cox regression analysis. RESULTS dNFKBIA was less frequently observed in KNBTG (47 cases, 22.2%) than in TCGA (84 cases, 31.7%). dNFKBIA was associated with unfavorable prognosis in KNBTG (HR 1.52, p = 0.031), while this was not validated in TCGA (HR 1.14, p=0.406). uMGMT was a common adverse prognostic factor in KNBGT (HR 1.72, p = 0.001) and TCGA (HR 1.50, p = 0.008) cohort. When stratified by NFKBIA status, uMGMT was also associated with shorter survival in NFKBIA deleted cases both in KNBTG (HR 1.87, p = 0.002) and TCGA (HR 1.59, p = 0.014). On the other hand, MGMT status was not significantly associated with prognosis in NFKBIA intact cases in either KNBTG (HR 1.45, p = 0.279) or TCGA (HR 1.55, p = 0.131). DISCUSSION Although the prognostic value of dNFKBIA in IDH wild-type GBM patients was not validated in TCGA cohort, our results indicated that the prognostication based on MGMT methylation was potentially interacted by NFKBIA status.


2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
Keng Lam ◽  
Blaine Eldred ◽  
Bryan Kevan ◽  
Matthew Ji ◽  
Jerry Lou ◽  
...  

Abstract BACKGROUND Patients with isocitrate dehydrogenase (IDH) mutant gliomas have been associated with longer survival time than those with IDH wildtype. Previous studies have also shown the predictive value of O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for glioblastoma. However, little is known in the prognostic value of MGMT methylation status for IDH mutant gliomas. METHODS We retrospectively identified IDH mutant gliomas patients from University of California Los Angeles and Kaiser Permanente Los Angeles that had been tested for MGMT methylation status. We performed Kaplan-Meier and Cox regression analyses of overall survival (OS) to compare the MGMT methylated versus MGMT unmethylated patients. RESULTS We identified a total of 375 IDH mutant gliomas with MGMT testing. Subgroups include 52 glioblastoma, 191 astrocytoma, and 132 oligodendroglioma. The median OS for all MGMT methylated patients was 20.0 years and for unmethylated patients 14.3 years (log-rank P=0.008). Cox regression analysis also confirmed patients with MGMT methylated to have better survival than those with MGMT unmethylated (hazard ratio of 0.47, P= 0.005). During subgroup analysis, MGMT methylated glioblastoma patients have a median OS of 13.7 years compared to MGMT unmethylated patients 3.2 years (log-rank P=0.004) with a hazard ratio of 0.14 (P=0.005). However, we see no difference yet for astrocytoma (hazard ratio of 1.09, P= 0.81) and oligodendrogliomas (hazard ratio of 0.36, P= 0.193), possibly as a result of immature survival data. CONCLUSIONS MGMT promoter methylation is associated with better outcomes in IDH mutant glioblastoma patients. Progression free survival will be analyzed to determine predictive benefit of MGMT methylation for other glioma subtypes.


2021 ◽  
Author(s):  
Haihang Zhang ◽  
Panpan Xie ◽  
Kaijia Shi ◽  
Danni Xu ◽  
Xingrui Cai ◽  
...  

Abstract Background: The prognostic value of N6-methylandenosine-related long non-coding RNAs (m6A-related lncRNAs) was investigated in 414 bladder cancer (BLCA) and 19 normal bladder tissue samples from The Cancer Genome Atlas (TCGA) datasets. Methods: We implemented Pearson correlation analysis to explore the lncRNAs associated with m6A, and then performed univariate Cox regression analysis to identify nine m6A-associated lncRNAs with prognostic value. The patients with BLCA were divided into two subgroups by consistency clustering. Analysis of the two groups of immune cell infiltration, immune microenvironment and clinical results were significantly different. We identified the prognostic significance of m6A-related lncRNAs by bioinformatic and statistical analysis of data from patients with BLCA.Results: We constructed an m6A-related lncRNA prognostic signature (m6A-LPS, including AL136295.2, AC104564.3, ATP1B3-AS1, EHMT2-AS1 and AC116914.2) to predict the OS of BLCA patients. It is proved that m6A LPS has independent prognostic value.


Blood ◽  
1983 ◽  
Vol 61 (5) ◽  
pp. 867-870 ◽  
Author(s):  
CW Jackson ◽  
GV Dahl

Abstract Small megakaryocytes are frequently seen in patients with acute nonlymphocytic leukemia (ANLL). In this study, median megakaryocyte diameters were determined in marrow biopsy specimens of 32 children at diagnosis of ANLL and related to platelet count and chemotherapeutic response. The association between median megakaryocyte size and time-to- failure was striking. Seven of 9 patients with median megakaryocyte diameters greater than 20 microns remain in continuous complete remission for more than 3 yr, whereas 20 of 23 patients with smaller median megakaryocyte diameters failed therapy within 15 mo (p = 0.002). By Cox-regression analysis, megakaryocyte size had independent prognostic value (p less than 0.001), surpassing that of spleen size, the only other feature having significant association with time-to- failure. Megakaryocyte size at diagnosis may be useful for predicting the likelihood of prolonged complete remission in ANLL.


2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Belkin ◽  
D Wussler ◽  
I Strebel ◽  
E Michou ◽  
N Kozhuharov ◽  
...  

Abstract Background Previous studies have shown the prognostic value of health-related quality of life (HRQL) in stable and ambulatory chronic heart failure patients. However, it is unknown whether HRQL can predict all-cause mortality in patients presenting to the emergency department (ED) after acute onset of symptoms. In order to address this unmet need, the aim of this study was to assess the prognostic value of HRQL in patients with acute dyspnea caused by acute heart failure (AHF) and other dyspnea aetiologies for 360-day mortality. Purpose To assess prognostic value of HRQL using the generic EQ-5D and visual analogue scale (EQ VAS) in patients with acute dyspnea. Methods Basics in Acute Shortness of Breath EvaLuation (BASEL V) is a prospective, multicenter, diagnostic study enrolling adult patients presenting with acute dyspnea to the ED. For this analysis, only patients with a complete set of variables necessary for calculation of EQ-5D (range 0–10; with higher score indicating worse HRQL) and EQ VAS (range 0–100; with 100 being the best imaginable health state) at baseline were included. The endpoint was the prognostic value of EQ-5D and EQ VAS at 360 days of follow-up regarding all-cause death. Prognostic accuracy was calculated using c-statistics. In a cox regression analysis EQ-5D was treated as both, a continuous and categorical variable. Adjustments were made for clinically relevant covariates (age, sex, orthopnoea, edema, level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) at presentation, history of coronary artery disease and chronic obstructive pulmonary disease, diuretics, β-blockers and ACE-inhibitors at discharge). Results Among 2605 patients enrolled, 1141 (43,8%) had a complete set of variables allowing the calculation of EQ-5D and EQ VAS. Of these patients 594 (52.1%) had an adjudicated final diagnosis of AHF. 211 (18.5%) patients died within 360 days of follow-up. Median EQ-5D was 3 (interquartile range (IQR) 1.5–5) and median EQ VAS was 50 (IQR 40–70). The prognostic accuracy for 360-day mortality was 0.65 (95% confidence interval ((CI) 0.61–0.69) and 0.58 (95% CI 0.54–0.62) for EQ-5D and EQ VAS, respectively (p=0.002). After combining EQ-5D and EQ VAS in a logistic regression model c-statistics regarding all-cause mortality within 360 days did not improve. The prognostic accuracy of EQ-5D was comparable to that of NT-proBNP (c-statistics 0.69, p=0.385). In an adjusted cox regression analysis the hazard ratio for patients with EQ-5D &gt;4 was 2.2 (95% CI 1.7–2.9; p&lt;0.001). Conclusions In patients presenting with acute dyspnea HRQL is a strong prognostic instrument. Independently of the aetiology of the dyspnea the prognostic value of the generic EQ-5D for 360-day mortality is comparable to NT-proBNP. Patients with an EQ-5D &gt;4 are at significantly higher risk for mortality within 360 days. Figure 1. Prognostic value of HRQL Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation, Swiss Heart Foundation


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