Methylation of tumor suppressor genes in a novel panel predicts clinical outcome in paraffin-embedded bladder tumors

Abstract

DNA methylation of tumor suppressor genes (TSGs) represents a frequent and early epigenetic event with potential applications for cancer detection and disease evolution. Our aim was to examine the stratification and prognostic biomarker role of the methylation of a novel panel of TSGs in bladder cancer. The methylation status of 18 TSGs was evaluated in bladder cancer cells (n=14) and paraffin-embedded primary bladder tumors (n=61), using a methylation-specific multiplex ligation-dependent probe amplification assay (MS-MLPA). Recurrence, progression, and disease-specific survival were analyzed using univariate and multivariate Cox models. PRDM2, HLTF, ID4, DLC1, BNIP3, H2AFX, CACNA1G, TGIF, and CACNA1A were discovered methylated in bladder cancer. The methylation of RUNX3 (p=0.026), TWIST1 (p=0.009), SFRP4 (p=0.002), and CCND2 (p=0.027) correlated to tumor stage. Univariate analyses indicated prognostic associations for recurrence (DLC1, SFRP5, H2AFX, CACNA1G), progression (DLC1, SFRP5, CACNA1G), disease-specific (PRDM2, DLC1, SFRP5, CACNA1G, and TIMP3), and overall survival (SFRP5 and TIMP3). In multivariate analyses, several TSGs remained as independent prognosticators for recurrence (SFRP5, H2AFX), progression (CACNA1G), and disease-specific survival (SFRP5). Thus, a novel set of TSGs was identified, frequently methylated in bladder cancer cells and tumors. TSG methylation allowed histopathologic and outcome stratification using paraffin-embedded tumors. This is clinically relevant by offering a strategy for the management of patients affected with uroepithelial neoplasias in pathology routine laboratories.

The prognostic role of epigenetic dysregulation in bladder cancer: A systematic review

“…Sánchez-Carbayo from CNIO (Spanish National Cancer Research Centre) in Madrid [13][14][15][16][17][18][19][20][21], of which four were focused on NMIBC [13][14][15][16]. Secondly, four out of five British studies were led by Dr. James Catto, from the University of Sheffield [22][23][24][25].…”

ID4 Promotes Breast Cancer Chemotherapy Resistance via CBF1-MRP1 Pathway

“…Sometimes it is an oncogene. Its over-expression promotes the occurrence and development of tumors such as astrocytoma and bladder cancer [27][28][29][30]. It is also regarded as a tumor suppressor gene because the methylation of ID4 promoter gene leading to ID4 silencing can also promote the development of colon cancer, gastric cancer, prostate cancer and hematological malignancies [31][32][33][34].…”

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

“…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 .…”