Login to Access Video or Poster Abstract: MP48-10
Sources of Funding: Not applicable.

Introduction

There is a well-established relationship between oxidative stress and the development and progression of bladder cancer. Prior clinical trials have shown a decrease in bladder cancer recurrence in patients on a high dose anti-oxidant vitamin regimen. In a previous integrative analysis of TCGA methylation data, we found genes in the Nrf2 pathway, an important regulatory pathway in response to oxidative stress, to be hyper-methylated and thus down regulated in bladder cancer. We sought to further characterize the activity of Nrf2 pathway gene expression in normal urothelium, and urothelium with non-muscle invasive and muscle invasive cancer.

Methods

We identified a publically available gene expression microarray dataset using the gene expression omnibus (GSE 3167) that included 10 patients with normal urothelium, 15 patients with stage Ta urothelial carcinoma, 8 patients with carcinoma in situ, and 13 patients with muscle invasive disease. We used the Nrf2 pathway signature discovered in our initial analysis. We evaluated the clustering of samples according to the Nrf2 pathway in an unsupervised pathway using the heatmap.2 function in R.

Results

Our clustering analysis on an independent dataset showed that the Nrf2 signature separates urothelial carcinoma from normal samples. The genes driving this clustering included KEAP1, GPX3, PGO, and TXN, all of which had higher levels of expression in normal tissue compared with tumor tissue, consistent with downregulation of Nrf2 dependent genes in tumor tissue. There did appear to be some independent clustering of low grade and muscle invasive disease, but this was less pronounced than the clustering of normal urothelium versus urothelial carcinoma.

Conclusions

This study corroborates prior findings and shows that genes in the Nrf2 pathway are inactivated in urothelial carcinoma. The expression of Nrf2 genes was decreased in patients with urothelial carcinoma. The lack of clear clustering among different stages of disease suggests that decreased expression of genes in the Nrf2 pathway is an early event in the pathogenesis of urothelial carcinoma. Our data demonstrate a biochemical description of the pathway by which antioxidant mechanisms may affect progression of urothelial carcinoma.

Funding

Not applicable.