The inflammation-to-carcinoma sequence is common in the development of prostate cancer (PCa). Inherited mutations in acute inflammatory genes such as tumor suppressor RNaseL influence the susceptibility of prostate cells to infection and are associated with increased risk for PCa. However, these mutations are rare, low penetrant and account for less than 2% of all PCa. In contrast, common genetic variations, such as low penetrant single nucleotide polymorphisms (SNP) in a large group of genes, are more likely to contribute to majority of sporadic prostate cancer cases. 2'-5'Oligoadenylate synthetase 1 (OASI), an androgen and IFN regulated gene within the inflammatory pathway converts ATP to 2'-5'-oligoadenylates (2-5A) which in turn activates RNaseL. Thus OASI is a rate limiting enzyme involved in generating RNaseL dependent anti-tumor response. Our studies have demonstrated that OASI is inversely correlated with increasing grade of PCa and that a functional nonsynonymous genetic variation in OASI is associated with PCa risk. However, significant questions regarding the effect of OASI genetic variations on survival and its mechanism of action in prostate cancer remains to be investigated. In order to address these questions we propose our hypothesis that

Public Health Relevance

OASI, alone or in association with RNaseL could be a prostate cancer susceptibility gene in general and African American population in perticular. Lack of OASI is expected to increase susceptibility to infections, suppress anti-tumor acute inflammatory response and promote prostate cancer. Loss of 0AS1 will also provide mechanistic basis for sporadic prostate cancer cases in which no RNaseL mutations are observed.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Exploratory Grants (P20)
Project #
5P20MD002285-07
Application #
8552128
Study Section
Special Emphasis Panel (ZMD1-RN)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
7
Fiscal Year
2013
Total Cost
$157,353
Indirect Cost
$46,945
Name
Clark Atlanta University
Department
Type
DUNS #
065325177
City
Atlanta
State
GA
Country
United States
Zip Code
30314
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