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 """"""""OASI expression or enzyme activity required to generate an anti-tumor response independently or as part of the RNaseL pathway is absent or attenuated in prostate cancer due to single nucleotide polymorphism and leads to increased morbidity and mortality specifically in African American population"""""""".
Two specific aims are proposed: 1. Investigate the association between OASI germ line variations with prostate cancer and racial disparity and 2. Investigate the biological significance of OAS1 in prostate cancer. Association studies from our laboratory have shown that a specific OASI genotype (rs2660: GG) that protects against prostate cancer is not present in a large cohort of African American population. These results are particularly interesting since racial disparities exist between prostate cancer incidence/ survival indicating intrinsic differences in genetics and tumor biology.
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.
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