Hypermethylation of E-cadherin, p16, p14, and RASSF1A genes in pathologically normal urothelium predict bladder recurrence of bladder cancer after transurethral resection

Lin, Hui‐Hui; Ke, Hung‐Lung; Wu, Wen‐Jeng; Lee, Ying-Huei; Chang, Lin‐Li

doi:10.1016/j.urolonc.2010.01.002

Cited by 25 publications

(13 citation statements)

References 11 publications

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“…The two ends of the dotted lines represent the 95% CI. studied epigenetic change in human cancer (Lin et al, 2012). Silencing of the CDH1 gene by DNA methylation around the promoter region in human carcinomas occurs frequently, including bladder cancer (Bornman et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Several previous studies have suggested that DNA methylation of CDH1 gene might be a reliable predictor of tumor progression in bladder cancer (Chan et al, 2002;Ribeiro-Filho et al, 2002;Friedrich et al, 2005;Pu et al, 2006;Yates et al, 2007). However, there are also some contradictory conclusions in the literatures concerning the prognostic value of CDH1 DNA methylation in the development and progression of bladder cancer (Bornman et al, 2001;Sun et al, 2009;Lin et al, 2012). The controversial findings are probably related to the effects from interacting with other genes, environmental effects on DNA methylation, different methods of classification, sample sizes, and study design.…”

Section: Introductionmentioning

confidence: 99%

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Role of CDH1 Promoter Polymorphism and DNA Methylation in Bladder Carcinogenesis: A Meta-Analysis

Wang

Kong²,

Zhang³

et al. 2014

DNA and Cell Biology

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Increasing scientific evidences suggest that CDH1 gene promoter polymorphism and DNA methylation may contribute to the development and progression of bladder cancer, but many existing studies have yielded inconclusive results. This meta-analysis aims to assess the role of CDH1 gene promoter polymorphism and methylation in bladder carcinogenesis. An extensive literature search for relevant studies was conducted in PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through April 1, 2013. This meta-analysis was performed using the STATA 12.0 software. The crude odds ratio with 95% confidence interval was calculated. Fifteen studies were included in this meta-analysis with a total of 824 bladder cancer patients and 818 healthy controls being assessed. Our meta-analysis revealed that the A variant of CDH1 -160C/A polymorphism was associated with an increased risk of bladder cancer. Further analysis by pathological subtype indicated that patients with invasive carcinoma had a higher frequency of CDH1 -160A variant than those with superficial carcinoma. We analyzed the methylation frequency of CDH1 gene in 608 bladder cancer samples and 338 normal bladder samples. Our data strongly suggest that the CDH1 promoter methylation frequencies in bladder cancer tissues were greater than those in normal control tissues. In conclusion, our meta-analysis indicates that promoter polymorphism and methylation of CDH1 gene may be involved in the development and progression of bladder cancer. CDH1 gene promoter polymorphism and methylation might be promising biomarkers for the diagnosis and prognosis of bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of CDH1 Promoter Polymorphism and DNA Methylation in Bladder Carcinogenesis: A Meta-Analysis

Wang

Kong²,

Zhang³

et al. 2014

DNA and Cell Biology

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“…54,55 UTI-induced CDKN2A methylation could provide a mechanism for the observed correlation between recurrent UTI and bladder carcinoma risk. [56][57][58] After infection, bladder uroepithelial cells undergo apoptosis that results in shedding of infected cells and intracellular pathogens, thereby reducing the overall pathogen load. Cell proliferation of basal cells increases and is followed by cell differentiation to replace lost uroepithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells

Tölg

Sabha

Cortese

et al. 2011

Laboratory Investigation

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Host cell and bacterial factors determine severity and duration of infections. To allow for bacteria pathogenicity and persistence, bacteria have developed mechanisms that modify expression of host genes involved in cell cycle progression, apoptosis, differentiation and the immune response. Recently, Helicobacter pylori infection of the stomach has been correlated with epigenetic changes in the host genome. To identify epigenetic changes during Escherichia coli induced urinary tract infection (UTI), we developed an in vitro model of persistent infection of human uroepithelial cells with uropathogenic E. coli (UPEC), resulting in intracellular bacteria colonies. Cells inoculated with FimH-negative E. coli (N-UPEC) that are not internalized and non-inoculated cells were used as controls. UPEC infection significantly induced de novo methyltransferase (DNMT) activity (12.5-fold P ¼ 0.002 UPEC vs non-inoculated and 250-fold P ¼ 0.001 UPEC vs N-UPEC inoculated cells) and Dnmt1 RNA expression (6-fold P ¼ 0.04 UPEC vs non-inoculated cells) compared with controls. DNMT1 protein levels were significantly increased in three uroepithelial cell lines (5637, J82, HT-1197) in response to UPEC infection as demonstrated by confocal analysis. Real-time PCR analysis of candidate genes previously associated with bacteria infection and/or innate immunity, revealed UPEC-induced downregulation of the tumor suppressor gene CDKN2A (3.3-fold P ¼ 0.007 UPEC vs non-inoculated and 3.3-fold P ¼ 0.001 UPEC vs N-UPEC) and the DNA repair gene MGMT (9-fold P ¼ 0.03 UPEC vs non-inoculated). Expression of CDH1, MLH1, DAPK1 and TLR4 was not affected. Pyrosequencing of CDKN2A and MGMT CpG islands revealed increased methylation in CDKN2A exon 1 (3.8-fold P ¼ 0.04 UPEC vs N-UPEC and UPEC vs non-inoculated). Methylation of MGMT was not affected. UPEC-induced methylation of CDKN2A exon 1 may increase bladder cancer and presage UTI risk, and be useful as a biological marker for UTI susceptibility or recurrence.

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“…The field effect theory asserts the entire urothelium in patients with UC may be unstable, due to genetic hits and progressive outgrowth of genetically unstable cells throughout the entire urothelium. Findings consistent with possible field effects in multifocal UC include promoter methylation of cancer-associated genes in histologically normal urothelium adjacent to UC[16], such as E-cadherin promoter methylation in the urothelium of elderly patients[4], as well as widespread TP53 mutations in the urothelium of patients with high level radiation exposure[28]. The clonal expansion theory states a single neoplastic clone is responsible for multi-focal disease and recurrence.…”

Section: Introductionmentioning

confidence: 99%

Tumor evolution and progression in multifocal and paired non-invasive/invasive urothelial carcinoma

et al. 2014

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Although multifocal tumors and non-invasive/invasive components are commonly encountered in surgical pathology, their genetic relationship is often poorly characterized. We used next generation sequencing (NGS) to characterize somatic alterations in a patient with five spatially distinct, high grade papillary urothelial carcinomas (UC), with one tumor harboring an underlying invasive component. NGS of 409 cancer related genes was performed on DNA isolated from formalin fixed paraffin embedded (FFPE) blocks representing each papillary tumor (n=5), the invasive component of one tumor, and matched normal tissue. We identified 9 unique non-synonymous somatic mutations across the six UC samples, including five present in each carcinoma sample, consistent with clonal origin and limited intertumoral heterogeneity. Copy number and loss of heterogeneity (LOH) profiles were similar in all six carcinomas; however, the invasive carcinoma component uniquely showed focal CDKN2A loss and chromosome 9 LOH, and did not harbor gains of chromosomes 5p or X that were present in the other tumor samples. Phylogenetic analysis supported the invasive component arising from a shared progenitor prior to the outgrowth of cells in the non-invasive tumors. Results were extended to three additional cases of upper tract UC with paired non-invasive/ invasive components, which identified driving alterations exclusive to both non-invasive and invasive components. Lastly, we performed targeted RNAseq using a custom bladder cancer panel, which confirmed gene expression signature differences between paired non-invasive/invasive components. The results and approaches presented here may be useful in understanding the clonal relationships in multifocal cancers or paired non-invasive/invasive components from routine FFPE specimens.

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Hypermethylation of E-cadherin, p16, p14, and RASSF1A genes in pathologically normal urothelium predict bladder recurrence of bladder cancer after transurethral resection

Cited by 25 publications

References 11 publications

Role of CDH1 Promoter Polymorphism and DNA Methylation in Bladder Carcinogenesis: A Meta-Analysis

Role of CDH1 Promoter Polymorphism and DNA Methylation in Bladder Carcinogenesis: A Meta-Analysis

Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells

Tumor evolution and progression in multifocal and paired non-invasive/invasive urothelial carcinoma

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