Altered Immune/Inflammatory Pathway in Racially Diverse Prostate Cancers

项目总结(见说明书)：炎症到癌的序列在前列腺癌(PCa)的发展过程中很常见。急性炎症基因的遗传突变，如肿瘤抑制基因RNASEL，会影响前列腺细胞对感染的易感性，并与前列腺癌风险增加有关。然而，这些突变很罕见，渗透率低，在所有PCa中所占比例不到2%。相比之下，常见的遗传变异，如一大组基因中的低穿透性单核苷酸多态(SNP)，更有可能导致大多数散发性前列腺癌病例。2‘-5’-寡腺苷合成酶1(OASI)是炎症途径中雄激素和干扰素调节的基因，它将ATP转化为2‘-5’-寡腺苷(2-5A)，进而激活RNASL。因此，OASI是一种限速酶，参与产生RNASL依赖的抗肿瘤反应。我们的研究表明，OASI与PCa分级呈负相关，OASI中的功能性非同义遗传变异与PCa风险相关。然而，关于OASI基因变异对前列腺癌生存率的影响及其作用机制的重大问题仍有待调查。为了解决这些问题，我们提出了我们的假设

PROJECT SUMMARY (See instructions): 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