Epigenetic changes have a key role in chemotherapy resistance in bladder cancer

A new study of neoadjuvant cisplatin-based chemotherapy showed that epigenetic changes are potential key drivers in the development of chemotherapy resistance in bladder cancer.

Neoadjuvant cisplatin-based chemotherapy is recommended for patients with muscle-invasive bladder cancer. Researchers,led by W. Tan of the Department of Surgery and Interventional Science of the University College London, stated that the ability to identify a biomarker that is able to predict response to treatment would increase pathological complete response rates, and would spare nonresponders from the adverse events of chemotherapy. DNA hypermethylation, a form of epigenetic changes, has been implicated in chemotherapy resistance in cancers.

"We hypothesized that DNA methylation may not only represent the mechanisms for the acquisition of resistance, but may also be a potential biomarker to predict response to platinum-based chemotherapy in bladder cancer," wrote Tan, lead author of the study titled "Epigenetic alterations associated with neoadjuvant chemotherapy resistance in bladder cancer," which was presented at the 28th Annual European Association of Urology Congress. The meeting was held in Milan, Italy, March 15-19, 2013.

In the study, DNA was extracted from 48 muscular invasive bladder tumors. These samples were taken prior to the patient receiving platinum-based neoadjuvant chemotherapy. All the tumors had greater than 80% tumor content. The research team generated genome-wide DNA methylation profiles by using the Infinium Human Methylation 450K BeadChip (Illumina).

According to the researchers, the analysis suggested that acquired resistance is associated with global hypermethylation in both primary tumors and paired cell lines. Singular value decomposition analysis revealed the strongest methylation signature to be associated with chemotherapy response (P ≤.001).

Supervised analysis identified about 2,700 methylation variable positions (MPVs) associated with chemotherapy responses. When the MVPs associated with chemotherapy response were hierarchically clustered, three clusters were defined: (1) chemosensitive, (2) chemoresistant, and (3) a mixed cluster with a hypomethylation phenotype. The MVPs associated with resistance include novel genes such as MEIS2, PROM1, and MAP1LC3A, as well as genes previously associated with resistance in other tumors, such as MEST and MLH1.

"These data suggest that epigenetic alterations are potential key drivers in the development of chemoresistance in bladder cancer. As well as providing novel insight into mechanisms of drug resistance, we have identified putative candidate biomarkers for further evaluation in future clinical studies, including potential stratification biomarkers in clinical trials of epigenetic therapies that reverse the acquired resistance phenotype," the researchers concluded.

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