Alterations of DNA methylome in human bladder cancer

Besaratinia, Ahmad; Cockburn, Myles; Tommasi, Stefania

doi:10.4161/epi.25927

Cited by 55 publications

(50 citation statements)

References 162 publications

(259 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, incomplete mapping of the genes might have occurred as a result of using a previous HapMap genome reference release or filtering by LD, what might have led to missing SNPs of interest. Finally, we did not explore all genetic mechanisms sustaining UBC prognosis, as the genetic architecture and correlations between genes involving complex interactions and epigenetic regulation are still unknown (50).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory-Related Genetic Variants in Non–Muscle-Invasive Bladder Cancer Prognosis: A Multimarker Bayesian Assessment

Masson-Lecomte

Maturana

Goddard

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

Background: Increasing evidence points to the role of tumor immunologic environment on urothelial bladder cancer prognosis. This effect might be partly dependent on the host genetic context. We evaluated the association of SNPs in inflammationrelated genes with non-muscle-invasive bladder cancer (NMIBC) risk-of-recurrence and risk-of-progression.Methods: We considered 822 NMIBC included in the SBC/ EPICURO Study followed-up >10 years. We selected 1,679 SNPs belonging to 251 inflammatory genes. The association of SNPs with risk-of-recurrence and risk-of-progression was assessed using Cox regression single-marker (SMM) and multimarker methods (MMM) Bayes A and Bayesian LASSO. Discriminative abilities of the models were calculated using the c index and validated with bootstrap cross-validation procedures.Results: While no SNP was found to be associated with risk-ofrecurrence using SMM, three SNPs in TNIP1, CD5, and JAK3

show abstract

Section: Discussionmentioning

confidence: 99%

Inflammatory-Related Genetic Variants in Non–Muscle-Invasive Bladder Cancer Prognosis: A Multimarker Bayesian Assessment

Masson-Lecomte

Maturana

Goddard

et al. 2016

Cancer Epidemiology, Biomarkers &Amp; Prevention

View full text Add to dashboard Cite

show abstract

“…Beside its involvement in normal development in human beings, DNA methylation is frequently implicated in the onset or course of cancer due to its roles in many other regulatory processes. Several studies have reported that aberrant promoter methylation at several gene loci was associated with bladder urothelial carcinoma (13,(25)(26)(27). As bladder urothelial carcinoma and UTUC display genomic and clinical similarities, we selected 10 genes (ABCC6, BRCA1, CDH1, GDF15, HSPA2, RASSF1A, SALL3, THBS1, TMEFF2 and VIM) with a high frequency of methylation in bladder urothelial carcinoma and evaluated their methylation statuses in UTUC and their associations with clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

Predictive value of gene methylation for second recurrence following surgical treatment of first bladder recurrence of a primary upper‑tract urothelial carcinoma

et al. 2018

View full text Add to dashboard Cite

Abstract. The clinical relevance of aberrant DNA promoter methylation is being increasingly recognized in urothelial carcinoma. The present study was conducted to explore the methylation status of patients with upper-tract urothelial carcinoma (UTUC) who experienced bladder recurrence, and to evaluate the predictive value of gene methylation for second bladder recurrence and tumor progression. A total of 85 patients with primary UTUC, who experienced bladder recurrence after radical nephroureterectomy, were enrolled between January 2001 and December 2013. Using methylation-sensitive polymerase chain reaction, the promoter methylation statuses of 10 genes were analyzed in the bladder tumor specimens. Among the patient group, 32 patients experienced second bladder recurrence, and bladder progression was detected in 16. With the exception of BRCA1, the methylation rate of the majority of genes tended to gradually increase to varying extents with the number of recurrences; a smaller proportion of primary tumors exhibited gene methylation when compared with the first recurrent tumors and second recurrent tumors. Univariate and multivariate Cox regression analyses revealed that unmethylated GDF15 [hazard ratio (HR)=0.36; 95% confidence interval (CI), 0.14-0.92] and methylated VIM (HR=2.91; 95% CI, 1.11-7.61) in the first recurrent bladder tumor, as well as male gender (HR=2.28; 95% CI, 1.06-4.87), first recurrence interval <8 months (HR=2.34; 95% CI, 1.15-4.78) and primary UTUC tumor size ≥5 cm (HR=3.48; 95% CI, 1.43-8.45) were independent risk factors for a second bladder recurrence after surgery for the first bladder recurrence; the Harrell's concordance index (c-index) for the related nomogram was 0.71 (95% CI: 0.61-0.81). Furthermore, methylated CDH1 (HR=2.91; 95% CI, 1.08-7.77) and VIM (HR=4.91; 95% CI, 1.11-21.7) in the first recurrent bladder tumor, male gender (HR=3.6; 95% CI, 1.1-11.73), and primary tumor stage T2-T4 (HR=4.57; 95% CI, 1.22-17.13), multifocality (HR=3.64; 95% CI, 1.19-11.16) and size ≥5 cm (HR=3.1; 95% CI, 1.91-10.54) for the primary UTUC were considered to be predictors of tumor progression; the c-index for the nomogram was 0.88 (95% CI, 0.69-0.92). The present findings demonstrated that promoter methylation of cancer-related genes was frequently observed in patients with urothelial carcinoma, and that the gene methylation rate of certain genes tended to gradually increase with the number of bladder recurrences. This may be used as a predictive factor for a second bladder recurrence and tumor progression after the surgical treatment of the first bladder recurrence.

show abstract

“…8,22,29 However, reports are limited and largely confined to heterogeneous patient cohorts of NMIBC or MIBC; 30 despite their clinical importance, highgrade NMIBC tumors are rarely investigated as a discrete entity in the context of disease and/or subtype-specific epigenetic modifications. 23 To address this, we performed genome-wide analyses of DNA methylation using BeadChip array technology in high-grade NMIBC, comprising a discrete cohort of tumors recruited at initial presentation.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, for some of the genes investigated, a significant inverse correlation between promoter methylation and gene expression levels was apparent and suggests their potential as targets for therapeutic intervention. 29,31,32 Initially we performed a technical validation of the discovery cohort data by pyrosequence analysis of converted DNA. 25,33,34 In common with previous reports and across multiple genes, these analyses confirmed and reinforced the array-derived data.…”

Section: Discussionmentioning

confidence: 99%

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

Kitchen¹,

Bryan²,

Emes³

et al. 2016

European Urology Supplements

View full text Add to dashboard Cite

High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease with greater risks of recurrence and progression relative to their low-intermediate-grade counterparts. The molecular events, including those affecting the epigenome, that characterize this disease entity in the context of tumor development, recurrence, and progression, are incompletely understood. We therefore interrogated genome-wide DNA methylation using HumanMethylation450 BeadChip arrays in 21 primary HG-NMIBC tumors relative to normal bladder controls. Using strict inclusion-exclusion criteria we identified 1,057 hypermethylated CpGs within gene promoter-associated CpG islands, representing 256 genes. We validated the array data by bisulphite pyrosequencing and examined 25 array-identified candidate genes in an independent cohort of 30 HG-NMIBC and 18 low-intermediate-grade NMIBC. These analyses revealed significantly higher methylation frequencies in high-grade tumors relative to lowintermediate-grade tumors for the ATP5G2, IRX1 and VAX2 genes (P<0.05), and similarly significant increases in mean levels of methylation in high-grade tumors for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, and HIST1H4F genes (P<0.05). Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumors. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination, with more conventional therapeutic options in the treatment of this clinically unpredictable disease.

show abstract

Alterations of DNA methylome in human bladder cancer

Cited by 55 publications

References 162 publications

Inflammatory-Related Genetic Variants in Non–Muscle-Invasive Bladder Cancer Prognosis: A Multimarker Bayesian Assessment

Inflammatory-Related Genetic Variants in Non–Muscle-Invasive Bladder Cancer Prognosis: A Multimarker Bayesian Assessment

Predictive value of gene methylation for second recurrence following surgical treatment of first bladder recurrence of a primary upper‑tract urothelial carcinoma

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

Contact Info

Product

Resources

About