Altered Immune/Inflammatory Pathway in Racially Diverse Prostate Cancers

炎症到癌的序列在前列腺癌(PCa)的发展过程中是常见的。继承 急性炎症基因突变，如肿瘤抑制基因RNASE L影响易感性 前列腺细胞易感染，并与前列腺癌的风险增加有关。然而，这些突变是罕见的， 渗透率低，占所有PCA的不到2%。相比之下，常见的遗传变异，如Low 一大组基因中的穿透性单核苷酸多态(SNP)更有可能导致 散发性前列腺癌病例居多。 2‘-5’寡腺苷合成酶1(OASI)，雄激素和干扰素在炎症反应中的调节基因 该途径将ATP转化为2‘-5’-寡腺苷(2-5A)，进而激活RNASE。因此，OASI是一个 限速酶参与产生RNASE依赖的抗肿瘤反应。我们的研究已经 OASI与PCa分级呈负相关，且OASI的功能非同义词 OASI的遗传变异与前列腺癌风险相关。然而，关于以下方面的重大问题 OASI基因变异对前列腺癌患者生存率的影响及其作用机制仍有待进一步研究 被调查。为了解决这些问题，我们提出了我们的假设，即OASI表达或 独立或作为RNASL的一部分产生抗肿瘤反应所需的酶活性 前列腺癌中由于单核苷酸多态性导致通路缺失或减弱，导致 增加发病率和死亡率，特别是在非裔美国人中“。 建议：1.研究OASI胚系变异与前列腺癌和种族的关系 2.探讨OAS1在前列腺癌中的生物学意义。协会研究来自 我们的实验室已经证明，一种特殊的OASI基因(rs2660：gg)可以预防前列腺癌 在一大批非裔美国人中并不存在。这些结果特别有趣 由于前列腺癌发病率/存活率之间存在种族差异，表明 遗传学和肿瘤生物学。

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.