Genome-wide analysis of CGIs in bladder cancer identifies novel epigenetic biomarkers for diagnosis and follow-up

Kandimalla, Raju; Tilborg, Angela van; Kompier, Lucie C.; Stumpel, Dominique J.P.M.; Zwarthoff, Ellen C.

doi:10.1016/j.cancergencyto.2010.07.042

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“…Up to now, no sensitive markers are available to predict progression in this specific patient group. Recently, Kandimalla et al 16 , proved the prognostic ability of the methylation markers TBX2, TBX3, GATA2, and ZIC4 using freshfrozen tumor tissue. 16 In this more extensive validation, these markers again proved to be highly sensitive for prediction of progression in low-grade pTa disease.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Kandimalla et al 16 , proved the prognostic ability of the methylation markers TBX2, TBX3, GATA2, and ZIC4 using freshfrozen tumor tissue. 16 In this more extensive validation, these markers again proved to be highly sensitive for prediction of progression in low-grade pTa disease. Patients with low methylation percentages of TBX2, TBX3, GATA2, and ZIC4 showed better progression-free survival in univariate logrank analysis.…”

Section: Discussionmentioning

confidence: 99%

“…As described by Kandimalla et al, 16 DNA was treated with sodium bisulfite, followed by a bisulfitespecific PCR for the four regions of interest. For each PCR reaction a DNA input of 10 ng and a PCR primer concentration of 20 pM was required.…”

Section: Dna Isolation and Methylation Analysismentioning

confidence: 99%

“…For each gene, the methylation percentage was calculated by dividing the height of the methylated peak by the sum of the height of the methylated and unmethylated peaks multiplied by 100%. 16 …”

Section: Dna Isolation and Methylation Analysismentioning

confidence: 99%

“…[13][14][15] Recently, Kandimalla et al 16 studied genome-wide hypermethylation of CpG islands in association with tumor progression. They investigated 238 unique CpG islands in pTaG1/2 tumors with and without disease progression, ie progression to muscle-invasive disease, metastasis or dead of disease.…”

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Stratification based on methylation of TBX2 and TBX3 into three molecular grades predicts progression in patients with pTa-bladder cancer

et al. 2015

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The potential risk of recurrence and progression in patients with non-muscle-invasive bladder cancer necessitates followup by cystoscopy. The risk of progression to muscle-invasive bladder cancer is estimated based on the European Organisation of Research and Treatment of Cancer score, a combination of several clinicopathological variables. However, pathological assessment is not objective and reproducibility is insufficient. The use of molecular markers could contribute to the estimation of tumor aggressiveness. We recently demonstrated that methylation of GATA2, TBX2, TBX3, and ZIC4 genes could predict progression in Ta tumors. In this study, we aimed to validate the markers in a large patient set using DNA from formalin-fixed and paraffin-embedded tissue. PALGA: the Dutch Pathology Registry was used for patient selection. We included 192 patients with pTaG1/2 bladder cancer of whom 77 experienced progression. Methylation analysis was performed and log-rank analysis was used to calculate the predictive value of each methylation marker for developing progression over time. This analysis showed better progression-free survival in patients with low methylation rates compared with the patients with high methylation rates for all markers (Po0.001) during a followup of ten-years. The combined predictive effect of the methylation markers was analyzed with the Coxregression method. In this analysis, TBX2, TBX3, and ZIC4 were independent predictors of progression. On the basis of methylation status of TBX2 and TBX3, patients were divided into three new molecular grade groups. Survival analysis showed that only 8% of patients in the low molecular grade group progressed within 5 years. This was 29 and 63% for the intermediate-and high-molecular grade groups. In conclusion, this new moleculargrade based on the combination of TBX2 and TBX3 methylation is an excellent marker for predicting progression to muscle-invasive bladder cancer in patients with primary pTaG1/2 bladder cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Dna Isolation and Methylation Analysismentioning

confidence: 99%

Section: Dna Isolation and Methylation Analysismentioning

confidence: 99%

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