Promoter Hypermethylation in Tumour Suppressor Genes Shows Association with Stage, Grade and Invasiveness of Bladder Cancer

Jarmalaitė, Sonata; Jankevičius, Feliksas; Kurgonaite, Kristina; Suziedelis, Kestutis; Mutanen, Pertti; Husgafvel‐Pursiainen, Kirsti

doi:10.1159/000158665

Cited by 57 publications

(48 citation statements)

References 56 publications

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“…Several groups have reported methylation markers of progression (14,20,23,24,41,42). We identified and validated TBX4 as a promising candidate of disease progression, but in addition to TBX4, we also found markers reported previously.…”

Section: Discussionsupporting

confidence: 54%

“…The POU4F2 protein is a transcription factor encoded by a gene located at chromosome 4q31. 23. POU4F2 has been reported to be a multifunctional protein that interacts with cancer-related genes such as BRCA1 and TP53.…”

Section: Discussionmentioning

confidence: 99%

“…CpG sites within CpG islands are usually in an unmethylated state permissive to transcription in normal cells but become hypermethylated at certain promoters in cancers. Transcriptional inactivation by CpG island promoter hypermethylation is a well-established mechanism for gene silencing in cancer including bladder cancer (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), and aberrant methylation is associated with stage, grade of the tumors as well as recurrence rate and progression (19)(20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive Genome Methylation Analysis in Bladder Cancer: Identification and Validation of Novel Methylated Genes and Application of These as Urinary Tumor Markers

Reinert

Modin

Castaño

et al. 2011

Clinical Cancer Research

181

161

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Purpose: Epigenetic alterations are common and can now be addressed in a parallel fashion. We investigated the methylation in bladder cancer with respect to location in genome, consistency, variation in metachronous tumors, impact on transcripts, chromosomal location, and usefulness as urinary markers.Experimental Design: A microarray assay was utilized to analyze methylation in 56 samples. Independent validation was conducted in 63 samples by a PCR-based method and bisulfite sequencing. The methylation levels in 174 urine specimens were quantified. Transcript levels were analyzed using expression microarrays and pathways were analyzed using dedicated software.Results: Global methylation patterns were established within and outside CpG islands. We validated methylation of the eight tumor markers genes ZNF154 (P < 0.0001), HOXA9 (P < 0.0001), POU4F2 (P < 0.0001), EOMES (P ¼ 0.0005), ACOT11 (P ¼ 0.0001), PCDHGA12 (P ¼ 0.0001), CA3 (P ¼ 0.0002), and PTGDR (P ¼ 0.0110), the candidate marker of disease progression TBX4 (P < 0.04), and other genes with stage-specific methylation. The methylation of metachronous tumors was stable and targeted to certain pathways. The correlation to expression was not stringent. Chromosome 21 showed most differential methylation (P < 0.0001) and specifically hypomethylation of keratins, which together with keratin-like proteins were epigenetically regulated. In DNA from voided urine, we detected differential methylation of ZNF154 (P < 0.0001), POU4F2 (P < 0.0001), HOXA9 (P < 0.0001), and EOMES (P < 0.0001), achieving 84% sensitivity and 96% specificity.Conclusions: We initiated a detailed mapping of the methylome in metachronous bladder cancer. Novel genes with tumor, chromosome, as well as pathway-specific differential methylation in bladder cancer were identified. The methylated genes were promising cancer markers for early detection of bladder cancer. Clin Cancer Res; 17(17); 5582-92. Ó2011 AACR.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comprehensive Genome Methylation Analysis in Bladder Cancer: Identification and Validation of Novel Methylated Genes and Application of These as Urinary Tumor Markers

Reinert

Modin

Castaño

et al. 2011

Clinical Cancer Research

181

161

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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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“…Studies have shown that methylation status plays an important role in carcinogenesis in various organs, including NMIBC (ref. [21][22][23][24][25][26][27][28][29][30] ). Methylation status is a potent indicator for distinguishing patients responding to BCG from those who are failing to do so and who need the radical therapy approach 31,32 .…”

Section: Discussionmentioning

confidence: 99%

Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor

Hušek¹,

Pacovský²,

Chmelařová³

et al. 2017

BIOMED PAP

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, Milos Brodak aBackground and Aims. Genetic and epigenetic alterations play an important role in urothelial cancer pathogenesis. Deeper understanding of these processes could help us achieve better diagnosis and management of this life-threatening disease. The aim of this research was to evaluate the methylation status of selected tumor suppressor genes for predicting BCG response in patients with high grade non-muscle-invasive bladder tumor (NMIBC). Materials and Methods. We retrospectively evaluated 82 patients with high grade non-muscle-invasive bladder tumor (stage Ta, T1, CIS) who had undergone BCG instillation therapy. We compared epigenetic methylation status in BCGresponsive and BCG-failure groups. We used the MS-MLPA (Methylation-Specific Multiplex Ligation-Dependent Probe Amplification probe sets ME001 and ME004. The control group was 13 specimens of normal urotel (bladder tissue)). Results. Newly identified methylations in high grade NMIBC were found in MUS81a, NTRK1 and PCCA. The methylation status of CDKN2B (P=0.00312 ** ) and MUS81a (P=0.0191 * ) is associated with clinical outcomes of BCG instillation therapy response. CDKN2B and MUS81a unmethylation was found in BCG failure patients. Conclusion.The results show that the methylation status of selected tumor suppressor genes (TSGs) has the potential for predicting BCG response in patients with NMIBC high grade tumors. Tumor suppressor genes such as CDKN2b, MUS81a, PFM-1, MSH6 and THBS1 are very promising for future research.

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Promoter Hypermethylation in Tumour Suppressor Genes Shows Association with Stage, Grade and Invasiveness of Bladder Cancer

Cited by 57 publications

References 56 publications

Comprehensive Genome Methylation Analysis in Bladder Cancer: Identification and Validation of Novel Methylated Genes and Application of These as Urinary Tumor Markers

Comprehensive Genome Methylation Analysis in Bladder Cancer: Identification and Validation of Novel Methylated Genes and Application of These as Urinary Tumor Markers

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

Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor

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