Epigenetic mechanisms driving bladder cancer.

摘要

Successes in the clinic have opened up the era of epigenetic therapy in which the goal is to reactivate genes silenced inappropriately during carcinogenesis. The advantage of using epigenetic therapy to target defects in DNA methylation is that, unlike mutations in the DNA sequence, these alterations are reversible. The focus of this thesis was twofold; to further elucidate the role of epigenetic alterations in bladder tumorigenesis and determine whether they provide useful therapeutic targets for epigenetic therapy. An ideal therapy for bladder cancer would address many of the unique aspects of bladder cancer, such as preventing tumors in high-risk patients with a history of smoking, treating both noninvasive and invasive tumors even though they develop via two separate molecular pathways, and reducing the frequency of recurrences. Based on the findings in this thesis epigenetic therapy, specifically DNA methylation inhibitors, has the potential to address each of these concerns;Using aberrant DNA methylation at RUNX3 as a clock I have shown that bladder tumors from smokers have undergone more cell divisions and may have initiated earlier than tumors from nonsmokers. In addition, since RUNX3 methylation is present in early lesions, epigenetic therapy may be useful in preventing high-risk patients from developing tumors. Epigenetic therapy also has the potential for treating both noninvasive and invasive bladder tumors since aberrant hypermethylation occurs at numerous gene promoters in both tumor types. I have also revealed the presence of a generalized epigenetic defect across bladders with cancer that is not due to clonal expansion. These epigenetic defects involve hypermethylation of single copy genes and also hypomethylation of specific LINE-1 elements. The hypomethylation of specific LINE-1 elements activates alternate transcripts of genes across the bladder, including the MET oncogene. The presence of so many epigenetic alterations in premalignant tissues of the bladder indicates that treatment with epigenetic therapy may be beneficial not just in the treatment of bladder tumors but also in the prevention of future recurrences.