Employing a bioinformatics approach to analyze prostate cancer gene expression profiles, we identified recurrent gene fusions/translocations in the majority of prostate cancers (Tomlins et al, Science 2005). Specifically, we identified the androgen regulatory elements of TMPRSS2 fused to the members of the ETS family of transcription factors including ERG, ETV1, ETV4 and ETV5. Analogous to hematological malignancies, gene fusions/translocations identified in prostate cancer may represent pathognomonic biomarkers and molecular sub-types of disease. In this application, we plan to focus our efforts on characterizing this new class of gene fusion biomarkers. Preliminary work done by our group and others suggest that molecular subtypes as well as transcript variants of gene fusions may be associated with clinical sub-types of prostate cancer. The central hypothesis of this application is that molecular sub-types based on gene fusions and variants will be useful predictors of the aggressive potential of clinically localized prostate cancer and thus guide treatment. Given this, we propose the following Aims:
Specific Aim 1 : Discovery and nomination of novel molecular sub-types of prostate cancer.
Specific Aim 2 : Characterize associations of molecular sub-types of prostate cancer with clinical outcome and/or aggressiveness of disease in a radical prostatectomy cohort.
Specific Aim 3. Characterize associations of molecular sub-types of prostate cancer with clinical outcome and/or aggressiveness of disease using prostate needle biopsy samples.

Public Health Relevance

Project Narrative: The discovery of genes fused together is a major advancement in the understanding of prostate cancer. This proposal is about using these "gene fusions" to identify prognostic categories to improve approaches to the treatment of prostate cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132874-04
Application #
8204900
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Martin, Damali
Project Start
2009-03-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$248,776
Indirect Cost
$87,756
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Feng, Felix Y; Brenner, J Chad; Hussain, Maha et al. (2014) Molecular pathways: targeting ETS gene fusions in cancer. Clin Cancer Res 20:4442-8
Kunju, Lakshmi P; Carskadon, Shannon; Siddiqui, Javed et al. (2014) Novel RNA hybridization method for the in situ detection of ETV1, ETV4, and ETV5 gene fusions in prostate cancer. Appl Immunohistochem Mol Morphol 22:e32-40
Smith, Steven C; Palanisamy, Nallasivam; Zuhlke, Kimberly A et al. (2014) HOXB13 G84E-related familial prostate cancers: a clinical, histologic, and molecular survey. Am J Surg Pathol 38:615-26
Cao, Qi; Wang, Xiaoju; Zhao, Meng et al. (2014) The central role of EED in the orchestration of polycomb group complexes. Nat Commun 5:3127
Malik, Rohit; Patel, Lalit; Prensner, John R et al. (2014) The lncRNA PCAT29 inhibits oncogenic phenotypes in prostate cancer. Mol Cancer Res 12:1081-7
Prensner, John R; Chen, Wei; Iyer, Matthew K et al. (2014) PCAT-1, a long noncoding RNA, regulates BRCA2 and controls homologous recombination in cancer. Cancer Res 74:1651-60
Roychowdhury, Sameek; Chinnaiyan, Arul M (2013) Advancing precision medicine for prostate cancer through genomics. J Clin Oncol 31:1866-73
Khan, Amjad P; Rajendiran, Thekkelnaycke M; Ateeq, Bushra et al. (2013) The role of sarcosine metabolism in prostate cancer progression. Neoplasia 15:491-501
Wu, Yi-Mi; Su, Fengyun; Kalyana-Sundaram, Shanker et al. (2013) Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov 3:636-47
Prensner, John R; Iyer, Matthew K; Sahu, Anirban et al. (2013) The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet 45:1392-8

Showing the most recent 10 out of 31 publications