The overall goal of this project is to develop novel biomarkers and diagnostic strategies for the early detection of occult urinary bladder neoplasia and its progression from intraurothelial preneoplastic conditions to invasive cancer. The current proposal represents an extension and logical continuation of the studies performed during the first cycle of the Early Detection Research Network (EDRN). These studies have led to the identification of six chromosomal regions critical for the development of bladder cancer and have provided evidence for the existence of a novel class of genes referred to as """"""""forerunners"""""""" whose involvement precedes the loss of function of major tumor suppressor genes in the development of cancer. We hypothesize that in situ clonal expansion of bladder preneoplasia is caused by loss of function of the forerunner genes mapping contiguously to known major tumor suppressors such as RB1. Our in vitro studies utilizing short interference RNA provide evidence that loss of function of these genes is critical for growth advantage of urothelial cells. Thus, the identification of novel forerunner genes and the investigation of their involvement in early occult phases of human bladder preneoplasia may not only provide important mechanistic clues to the development of human cancer but may also identify a novel class of early detection markers capable of detecting the clinically and microscopically occult phases of human cancer development. We also hypothesized a complementary mechanism of bladder cancer progression based on the amplification and overexpression of a recently identified oncogenic kinase STK15/BTAK/Aurora-A shown to be involved in regulating chromosomal segregation and centrosome function and more recently to be capable of destabilizing the p53 tumor suppressor protein. In this grant we propose the following major groups of studies: (1) Perform functional analyses and assessment of the already identified putative """"""""forerunner genes"""""""" (ITM2B, P2RY5, and CHClL) located contiguously to RB1 as novel early detection biomarkers. Additionally, we propose to characterize other predicted forerunner gene harboring loci mapping on chromosomes 17p13 and 5q22-23 and to assess the candidate genes identified as biomarkers for bladder cancer detection. We will also investigate the contribution of genetic and epigenetic mechanisms in the functional inactivation of each of the genes to elucidate a comprehensive view of the role of forerunner genes in the malignant transformation process that will enhance our ability to detect forerunner genes and provide clinically relevant markers for early detection. (2) Extension of our studies on STK15/BTAK/Aurora-A and its interacting genes involved in the pathway as biomarkers for bladder cancer detection. (3) Combine the STK15/BTAK/Aurora-A and its regulatory partners with the forerunner genes in a panel of approximately 15 markers testing their ability to identify occult bladder neoplasia in a prospective validation trial. Since both major categories of novel genes, i.e. the forerunner genes and Aurora-A with its partners, appear to be universally involved in human carcinogenesis the completion of this project will have major relevance for early detection of other common human cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA085078-09
Application #
7277613
Study Section
Special Emphasis Panel (ZCA1-SRRB-E (O1))
Program Officer
Kagan, Jacob
Project Start
1999-09-30
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
9
Fiscal Year
2007
Total Cost
$513,620
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pathology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Estécio, Marcos R H; Gallegos, Juan; Vallot, Céline et al. (2010) Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer. Genome Res 20:1369-82
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Majewski, Tadeusz; Lee, Sangkyou; Jeong, Joon et al. (2008) Understanding the development of human bladder cancer by using a whole-organ genomic mapping strategy. Lab Invest 88:694-721
Park, Hong-Seok; Park, Weon Seo; Bondaruk, Jolanta et al. (2008) Quantitation of Aurora kinase A gene copy number in urine sediments and bladder cancer detection. J Natl Cancer Inst 100:1401-11
Lee, Sangkyou; Jeong, Joon; Majewski, Tadeusz et al. (2007) Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia. Proc Natl Acad Sci U S A 104:13732-7
Kim, Mi-Sook; Jeong, Joon; Majewski, Tadeusz et al. (2006) Evidence for alternative candidate genes near RB1 involved in clonal expansion of in situ urothelial neoplasia. Lab Invest 86:175-90
Kim, Jai-Hyun; Tuziak, Tomasz; Hu, Limei et al. (2005) Alterations in transcription clusters underlie development of bladder cancer along papillary and nonpapillary pathways. Lab Invest 85:532-49

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