The objectives of this grant, which has been funded for almost 30 years, are to understand the genetic and epigenetic basis of human bladder cancer. We have defined the existence of two molecular pathways for the genesis of bladder cancer (UC) in which superficial (Ta/T1) tumors, which frequently recur, are distinct from more aggressive tumors at the molecular level. We have also shown profound epigenetic alterations which occur during bladder carcinogenesis and want to continue our studies by using more global approaches to define key genes which may play a role in this prevalent but understudied disease. In the next five year period of the grant, we will use a series of eight hypermethylation markers to complete the examination of DNA in urine sediments obtained from individuals with low grade tumors to determine whether we can detect the frequent recurrences of these tumors. We shall also complete the analysis of DNA from healthy individuals of different ages to determine whether age-related changes in DNA methylation can be detected in urine sediments. Secondly, using high-throughput approaches on the Illumina platform, we have observed a hypomethylation phenotype not seen in the apparently normal urothelium but particularly prevalent in superficial tumors and less frequently in more invasive tumors. This hypomethylation is seen in the vicinity of transcription start sites and might play a role in ectopic gene activation in tumors.
In Specific Aims 3 and 4 we will determine the functional significance of these changes by analyzing directly whether methylation of non- CpG island regions which constitute the bulk of the hypomethylation phenotype might be involved in gene activation and have chromatin properties associated with active genes. Finally, in Specific Aim 5 we will take advantage of ongoing clinical trials in which patients with myelodysplastic syndrome are being treated with the hypomethylating drug 5-azacytidine (5-aza-CR). Since we can easily and non-invasively obtain urine sediments from these patients, we can directly test the hypothesis that systemic administration of hypomethylating drugs leads to demethylation of bladder urothelial cells which may have implications in the future for treatment of this disease.

Public Health Relevance

Bladder cancer is the 5th most common cancer in the United States and is one of the most expensive cancers to treat because of its propensity to recur. We have discovered substantial epigenomic changes in low grade (Ta/T1) tumors which can be detected in urine sediments and might help steer clinical decisions associated with gene activation in the tumors, and shall investigate the mechanism for this action. We want eventually to develop epigenetic therapies for bladder cancer and shall take advantage of clinical trials in which patients who do not have this disease are being treated with demethylating agents to test the effects of these drugs on DNA methylation patterns in the normal urothelial cells of humans.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA083867-15
Application #
8657808
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Okano, Paul
Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Urology
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Becket, Elinne; Chopra, Sameer; Duymich, Christopher E et al. (2016) Identification of DNA Methylation-Independent Epigenetic Events Underlying Clear Cell Renal Cell Carcinoma. Cancer Res 76:1954-64
Duymich, Christopher E; Charlet, Jessica; Yang, Xiaojing et al. (2016) DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells. Nat Commun 7:11453
Charlet, Jessica; Duymich, Christopher E; Lay, Fides D et al. (2016) Bivalent Regions of Cytosine Methylation and H3K27 Acetylation Suggest an Active Role for DNA Methylation at Enhancers. Mol Cell 62:422-31
Lay, Fides D; Liu, Yaping; Kelly, Theresa K et al. (2015) The role of DNA methylation in directing the functional organization of the cancer epigenome. Genome Res 25:467-77
Su, Sheng-Fang; de Castro Abreu, André Luís; Chihara, Yoshitomo et al. (2014) A panel of three markers hyper- and hypomethylated in urine sediments accurately predicts bladder cancer recurrence. Clin Cancer Res 20:1978-89
Lay, Fides D; Triche Jr, Timothy J; Tsai, Yvonne C et al. (2014) Reprogramming of the human intestinal epigenome by surgical tissue transposition. Genome Res 24:545-53
Jones, Peter A (2014) At the tipping point for epigenetic therapies in cancer. J Clin Invest 124:14-6
Pandiyan, Kurinji; You, Jueng Soo; Yang, Xiaojing et al. (2013) Functional DNA demethylation is accompanied by chromatin accessibility. Nucleic Acids Res 41:3973-85
Yang, Xiaojing; Noushmehr, Houtan; Han, Han et al. (2012) Gene reactivation by 5-aza-2'-deoxycytidine-induced demethylation requires SRCAP-mediated H2A.Z insertion to establish nucleosome depleted regions. PLoS Genet 8:e1002604
Kelly, Theresa K; Liu, Yaping; Lay, Fides D et al. (2012) Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules. Genome Res 22:2497-506

Showing the most recent 10 out of 42 publications