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

Abstract

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.

Aberrant gene-specific DNA methylation signature analysis in cervical cancer

“…80 It is hypermethylated in bladder cancer and acts as pTa-specific prognostic marker. 81 TBX3 overexpression is also reported in a number of cancers. In melanoma, TBX3 overexpression is associated with promotion and invasion of melanoma, while in breast cancer, it is shown to interact with histone deacetylases (HDACs).…”

Enduring epigenetic landmarks define the cancer microenvironment

“…The tsDMRs transcend the considerable global differences in DNA methylation between each cell type, since, unlike CAFs, cancer cells undergo extensive hypomethylation (Hansen et al 2011;Berman et al 2012;Kretzmer et al 2015). Notably, the tsDMRs are strongly overrepresented in developmental gene families and genes involved in endocrine hormone secretion, such as TBX3 (Holterhus et al 2007;Beukers et al 2015), suggesting that they are associated with functional roles in cancer progression. Indeed specific tsDMRs were found in known tumor suppressor genes (for example, EHF [Albino et al 2012] and MCC [KohonenCorish et al 2007]) and oncogenes (for example, STEAP2 [Whiteland et al 2014]).…”

Positive association of collagen type I with non-muscle invasive bladder cancer progression

“…For instance, FGFR3 activating mutation associates with and is predictive of better prognosis [12–14], and abnormal expression of cytokeratin 20 positively associates with progression [15, 16]. Methylation of TBX2 and TBX3 genes are recently demonstrated to be predictive of progression [17]. Nevertheless, the tumor microenvironment, specifically alterations in the subepithelial stroma, during invasive progression of NMIBC remains largely unexplored.…”