Promoter Hypermethylation Identifies Progression Risk in Bladder Cancer

Abstract

Purpose: New methods to accurately predict an individual tumor behavior are urgently required to improve the treatment of cancer. We previously found that promoter hypermethylation can be an accurate predictor of bladder cancer progression, but it is not cancer specific. Here, we investigate a panel of methylated loci in a prospectively collected cohort of bladder tumors to determine whether hypermethylation has a useful role in the management of patients with bladder cancer. Experimental Design: Quantitative methylation-specific PCR was done at 17 gene promoters, suspected to be associated with tumor progression, in 96 malignant and 30 normal urothelial samples. Statistical analysis and artificial intelligence techniques were used to interrogate the results. Results: Using log-rank analysis, five loci were associated with progression to more advanced disease (RASSF1a, E-cadherin, TNFSR25, EDNRB, and APC ; P < 0.05). Multivariate analysis revealed that the overall degree of methylation was more significantly associated with subsequent progression and death (Cox, P = 0.002) than tumor stage (Cox, P = 0.008). Neuro-fuzzy modeling confirmed that these five loci were those most associated with tumor progression. Epigenetic predictive models developed using artificial intelligence techniques identified the presence and timing of tumor progression with 97% specificity and 75% sensitivity. Conclusion: Promoter hypermethylation seems a reliable predictor of tumor progression in bladder cancer. It is associated with aggressive tumors and could be used to identify patients with either superficial disease requiring radical treatment or a low progression risk suitable for less intensive surveillance. Multicenter studies are warranted to validate this marker.

SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer

“…These data suggest that transient activation of ZEB proteins triggers EMT, but its maintenance in growing tumors may require additional, possibly epigenetic mechanisms. This is in agreement with the notion that DNA methylation is involved in transcriptional silencing of E-cadherin gene in bladder cancer cell lines and in tumor tissues (26).…”

The origins of bladder cancer

“…Epigenetic predictive models using artificial intelligence also support the premise that promoter hypermethylation is a reliable predictor of tumor progression in bladder cancer. 29 Collectively, these data support the concept that cigarette smoke is not only a direct mutagenic carcinogen, but also associated with the genesis of epigenetic alterations in bladder cancer. 30 Continuous tobacco carcinogen exposure, in combination with increasing age and male gender, drives and enhances the selection and clonal expansion of epigenetically altered cells.…”

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

“…Yan et al 24 , showed that methylation of RUNX3 in combination with G3 increased the chance of disease progression. According to Yates et al 15 , methylation of E-cadherin, TNFRSF25, EDNRB, RASSF1A, and APC were significantly associated with progressive disease. Yet, these studies all used a mixture of pT1 and pTa tumors.…”

“…[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.…”