Multidiciplinary Integrative Genomic Approach to Distinguish Lethal from Indolent Prostate Cancer in Men of Europena and African Ancestry

 描述(由申请人提供)：在局限性前列腺癌的治疗中有几个关键的未得到满足的需求。其中的核心是开发微创工具，以区分真正惰性的局部癌症和进展性和潜在致命性的癌症。为了解决这一关键需求，我们首先建议进行集成的、多维的基因组、表观基因组和表达分析，以揭示表征惰性前列腺癌和侵袭性前列腺癌的新的分子途径。在这种方法中，我们将惰性肿瘤定义为根治性前列腺癌根治术中器官受限的Gleason评分为6(或更低)的筛查发现(如PSA筛查)病变。我们认为这些肿瘤是惰性的，因为它们似乎不能转移。相比之下，我们将Gleason评分8-10的肿瘤等同于“间歇性”或有症状的肿瘤，因为即使进行了初步治疗，这些肿瘤通常也会以高频率复发和转移。此外，我们将使用更多具有长期结果的种群来验证我们在该项目中发现的关键标记/路径。我们假设，我们的基于多模式基因组的综合方法，对比这两种不同的肿瘤类型，将揭示区分癌症和二分表型的特征。我们还假设，这些特征将根据种族的不同而不同，因此，我们将全面描述非裔美国人前列腺癌的特征，以揭示导致结果种族差异的分子特征。我们将使用已确定结果的大量病例队列来验证获得的签名，这些病例包括：(1)约翰·霍普金斯大学主动监测队列和(2)来自BLSA(巴尔的摩老龄化纵向研究)的前列腺癌病例，这是自1954年以来追踪的有身体解剖记录的惰性或侵袭性/致命疾病的男性的观察性队列。我们还提出，这些信号将能够以不确定的动力学预测癌症的结果，并建议通过分析具有长期随访和约翰·霍普金斯大学的已知结果的中等风险前列腺癌病例，以及与哈佛大学的同事合作，从医生的健康和健康专业人员后续研究中对此进行测试。总而言之，这项工作将产生高度相关的信息，可以直接应用于局限性前列腺癌的临床治疗。具体地说，它将产生一个集成的签名，以区分本地化的- 惰性肿瘤来源于局部的具有致死潜力的肿瘤。此外，我们认为这些信号将在确定前列腺癌患者的治疗策略时起到关键作用。

 DESCRIPTION (provided by applicant): There are several critical unmet needs in the management of localized prostate cancer. Central among them is the development of minimally invasive tools to distinguish localized cancers that are truly indolent from cancers that are progressive and potentially lethal. To address this key need, we first propose to perform an integrated, multi-dimensional genomic, epigenomic and expression analysis to uncover novel molecular pathways that characterize indolent vs. aggressive prostate cancers. In this approach we define indolent tumors as those screen detected (e.g. PSA screening) lesions that are Gleason score 6 (or less) that are organ confined at radical prostatectomy. We consider these tumors indolent as they do not appear capable of metastasis. In contrast, we equate Gleason score 8-10 tumors as "interval" or symptomatic since, even with primary treatment, these tumors often recur and metastasize at high frequencies. Additionally, we will validate our key markers/pathways discovered in this project using additional populations with long term outcomes. We hypothesize that our multi-modality genomic-based integrated approach, contrasting these two divergent tumor types, will reveal signatures that distinguish cancers with dichotomous phenotypes. We also hypothesize that these signatures will vary based on race and thus in parallel we will comprehensively characterize African American prostate cancers to reveal molecular features driving racial disparities in outcomes. We will validate the signatures obtained using large cohorts of cases with established outcomes including: (1) the Johns Hopkins Active surveillance cohort and (2) Prostate cancer cases from the BLSA (Baltimore Longitudinal Study of Aging), an observational cohort of men followed since 1954 with autopsy documented indolent or aggressive/lethal disease. We also propose that these signatures will be able to predict outcomes of cancers with indeterminate kinetics and propose to test this through analysis of cases of intermediate risk prostate cancer with long-term follow-up and known outcomes from Johns Hopkins and in collaboration with colleagues from Harvard, from the Physician's Health and Health Professionals follow-up studies. Together this work will yield highly relevant information that can be directly applied to the clinical management of localized prostate cancer. Specifically, it will yield an integrated signature that distinguishes localized - indolent tumors from localized tumors with lethal potential. Additionally we believe these signatures will be critical in determining treatment strategies for individuals with prostate cancers of indeterminate kinetics.