Evidence for the early onset of aberrant promoter methylation in urothelial carcinoma

Dhawan, Dipali; Hamdy, Freddie C.; Rehman, Ishtiaq; Patterson, Jacob M.; Cross, Simon S.; Feeley, K M; Stephenson, Y; Meuth, Mark; Catto, James W.F.

doi:10.1002/path.1991

Cited by 75 publications

(60 citation statements)

References 23 publications

(36 reference statements)

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“…23,24 The rate of methylation of RASSF1 that we detect in pure TCC and TCC with SCBC are similar to those in previous reports. 37,[46][47][48][49] However, the frequency of MGMT methylation in TCC with SCBC that we observed was significantly higher than the 2-5% rates reported in two prior studies comprising 196 combined specimens of pure TCC. 36,37 We believe this reflects an innate propensity for TCCs harboring MGMT methylation to develop clones of SCBC.…”

Section: Discussioncontrasting

confidence: 79%

Hypermethylation of tumor-suppressor gene CpG islands in small-cell carcinoma of the urinary bladder

et al. 2008

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Small-cell carcinoma of the urinary bladder (SCBC) is a rare tumor, which shows a common clonal origin with urothelial carcinoma. It bears a high metastatic potential, even when discovered in a localized state. Identifying the molecular underpinnings of this disease may elucidate useful clinical information regarding prevention, diagnosis, prognosis, treatment, and surveillance. As DNA methylation is widely recognized as having a pivotal role in the process of carcinogenesis, we analyzed the DNA methylation status of four frequently hypermethylated tumor suppressors in small-cell and transitional-cell carcinoma (TCC) arising concomitantly in 13 patients. Fourteen cases of pure TCC were also included in the analysis. We identified frequent methylation of RASSF1 and MGMT and infrequent methylation of MLH1 and DAPK1 in cases of concomitant TCC and SCBC. Similar rates of methylation were found in pure and concomitant histopathologies, with the exception of MGMT, which was much less frequently methylated in pure TCC. These findings suggest that SCBC and TCC have common origins, establish DNA methylation of some tumor suppressors as frequent occurrences in both histopathologies, and suggest that MGMT methylation may be an SCBC-specific epimutation. Modern Pathology (2008) 21, 355-362; doi:10.1038/modpathol.3801012; published online 11 January 2008Keywords: urinary bladder; small-cell carcinoma; DNA methylation; epigenetics DNA methylation-induced silencing of gene expression is now recognized as an important contributor in all stages of carcinogenesis. 1 Methylation of CpGdense regions, or CpG islands (CpGIs), associated with the first exons of many genes, serves to recruit transcriptional silencing machinery, including methyl-CpG-binding proteins, histone deacetylases and methyltransferases, and ATP-dependent chromatin-remodeling enzymes. 2,3 Silencing of key tumor and metastasis suppressors, 4,5 drug-metabolizing enzymes, 6 and DNA-repair proteins 7 is an event that contributes to carcinogenesis, acquisition of invasiveness and metastatic potential, angiogenesis, and therapy refractoriness. DNA methylation is a target for both therapeutic and biomarker purposes. 8 Importantly, the study of DNA methylation in clinical samples may provide useful and novel insights into the pathobiology of disease processes such as cancer.Transitional-cell carcinoma (TCC) arises from urothelium, which lines the bladder, as well as the renal pelvis, ureter, and portions of the urethra. Although infrequent in occurrence, small-cell bladder cancer (SCBC) may evolve or co-evolve from pre-existing TCC. 9 We hypothesized that DNA methylation of specific genes may underlie the pathogenesis of SCBC. In this study, we quantitatively analyzed the methylation status of RASSF1,

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Section: Discussioncontrasting

confidence: 79%

Hypermethylation of tumor-suppressor gene CpG islands in small-cell carcinoma of the urinary bladder

et al. 2008

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“…36 On the other hand, there is substantial evidence for the role of epigenetic silencing of genes by promoter hypermethylation in urinary bladder carcinogenesis (e.g., p16, sFRP, E-cadherin, DAPK and RASSF1A), [37][38][39][40][41][42][43][44] indicating that both genetical and epigenetical alterations contribute to bladder tumor development through multiple or stepwise carcinogenesis, as well as to the diversity of cancer cells in later progression stages. [36][37][38][39][40][41][42][43] Recently, a distinct group of cancers carrying frequent DNA hypermethylation on CpGislands has been identified and designated as a CIMP in a certain subset of colorectal and stomach malignancies. [45][46][47] In addition, Dr. Issa's group has reported in their colon cancer studies, that CIMP can be subclassified into cases with microsatellite instability and BRAF mutation (CIMP1) and with somatic KRAS mutation and rare microsatellite instability (CIMP2).…”

Section: Discussionmentioning

confidence: 99%

BAMBI gene is epigenetically silenced in subset of high‐grade bladder cancer

Khin

Kitazawa

Win³

et al. 2009

Intl Journal of Cancer

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The bone morphogenetic protein (BMP) and activin membranebound inhibitor (BAMBI) is a transmembrane TGFRI/BMPRIrelated pseudoreceptor, antagonizes transforming growth factor (TGF)-b/BMP signaling by inhibiting the formation of functional authentic receptor complexes (TGFRI/BMPRI and TGFRII/ BMPRII). On the assumption that BAMBI gene expression is epigenetically altered during human bladder cancer progression, we screened the expression of BAMBI protein by immunohistochemistry and the methylation status of the BAMBI promoter. In the normal or reactive urothelium, BAMBI expression was mostly overlapped with that of BMPRI, and a similar colocalization pattern was noted in low-grade papillary cancers. In high-grade and invasive cancers, however, mainly two reciprocal immunohistochemical expression patterns were observed: BAMBI-low/BMPRIhigh, and BAMBI-high/BMPRI-low, indicating that BAMBI expression is controlled such that it does not interfere with the responsiveness of high-grade cancer cells to TGF-b/BMP signaling. Moreover, methylation of the BAMBI gene correlated significantly with negative BAMBI expression in bladder tumors. Although BAMBI overexpression significantly increased the number of apoptotic cells in T24 line, knock-down small interfering RNA showed no remarkable change. Cell motility assay revealed that on treatment with either TGF-b1 or BMP2, T24 and HTB9 lines showed a marked increase in the number of migrated cells which, however, decreased significantly through the forced expression of BAMBI. Since certain subsets of aggressive tumors often promote cell motility, invasion and survival by inducing epithelial-to-mesenchymal transition through TGF-b/BMP in an autocrine and paracrine manner, hypermethylation of the BAMBI gene promoter that leads to BAMBI gene suppression may be one of the epigenetic events affecting the invasiveness or aggressiveness of bladder cancers. ' 2009 UICC

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“…We selected RNAs for analysis by using bisulfite sequencing from those in which 5-azacytdine induced altered expression and were adjacent to CpG islands and differentially methylated regions (DMR), from miRs found to be methylated in other tumors, and from RNAs located adjacent to both CpG islands and DMRs (12,13,18). Briefly, target CpG regions were amplified by using bisulfite-specific PCR, the products cleaned and cloned into Escherichia coli before sequencing (detailed in ref.…”

Section: Rna Expression and Methylation Of Cpg Dinucleotides And Adjamentioning

confidence: 99%

Hypermethylation of CpG Islands and Shores around Specific MicroRNAs and Mirtrons Is Associated with the Phenotype and Presence of Bladder Cancer

Dudziec

Miah

Choudhry

et al. 2011

Clinical Cancer Research

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Purpose: To analyze the role and translational potential for hypermethylation of CpG islands and shores in the regulation of small RNAs within urothelial cell carcinoma (UCC). To examine microRNAs (miR) and mirtrons, a new class of RNA located within gene introns and processed in a Drosha-independent manner.Experimental design: The methylation status of 865 small RNAs was evaluated in normal and malignant cell lines by using 5-azacytidine and microarrays. Bisulfite sequencing was used for CpG regions around selected RNAs. Prognostic and diagnostic associations for epigenetically regulated RNAs were examined by using material from 359 patients, including 216 tumors and 121 urinary samples (68 cases and 53 controls). Functional analyses examined the effect of silencing susceptible RNAs in normal urothelial cells.Results: Exonic/UTR-located miRs and mirtons are most susceptible to epigenetic regulation. We identified 4 mirtrons and 16 miRs with CpG hypermethylation across 35 regions in normal and malignant urothelium. For several miRs, hypermethylation was more frequent and dense in CpG shores than islands (e.g., miRs-9/149/210/212/328/503/1224/1227/1229), and was associated with tumor grade, stage, and prognosis (e.g., miR-1224 multivariate analysis OR ¼ 2.5; 95% CI, 1.3-5.0; P ¼ 0.006). The urinary expression of epigenetically silenced RNAs (miRs-152/328/1224) was associated with the presence of UCC (concordance index, 0.86; 95% CI, 0.80-0.93; ANOVA P < 0.016).Conclusions: Hypermethylation of mirtrons and miRs is common in UCC. Mirtrons appear particularly susceptible to epigenetic regulation. Aberrant hypermethylation of small RNAs is associated with the presence and behavior of UCC, suggesting potential roles as diagnostic and prognostic biomarkers.

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Evidence for the early onset of aberrant promoter methylation in urothelial carcinoma

Cited by 75 publications

References 23 publications

Hypermethylation of tumor-suppressor gene CpG islands in small-cell carcinoma of the urinary bladder

Hypermethylation of tumor-suppressor gene CpG islands in small-cell carcinoma of the urinary bladder

BAMBI gene is epigenetically silenced in subset of high‐grade bladder cancer

Hypermethylation of CpG Islands and Shores around Specific MicroRNAs and Mirtrons Is Associated with the Phenotype and Presence of Bladder Cancer

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