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）：在局部前列腺癌的治疗中存在一些未满足的关键需求。其中的核心是开发微创工具来区分真正惰性的局部癌症和进行性且可能致命的癌症。为了满足这一关键需求，我们首先建议进行集成的多维基因组、表观基因组和表达分析，以揭示表征惰性前列腺癌与侵袭性前列腺癌的新分子途径。在这种方法中，我们将惰性肿瘤定义为在根治性前列腺切除术中筛查发现（例如 PSA 筛查）格里森评分为 6（或更低）且器官受限的病变。我们认为这些肿瘤是惰性的，因为它们似乎不具备转移能力。相反，我们将格里森评分 8-10 的肿瘤视为“间期”或有症状的肿瘤，因为即使经过初步治疗，这些肿瘤也经常以高频率复发和转移。此外，我们将使用具有长期结果的其他人群来验证本项目中发现的关键标记/途径。我们假设，我们的基于多模态基因组的整合方法，对比这两种不同的肿瘤类型，将揭示区分具有二分表型的癌症的特征。我们还假设这些特征会因种族而异，因此同时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。我们将验证使用具有既定结果的大量病例队列获得的特征，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，这是一个自 1954 年以来跟踪的男性观察队列，尸检记录有惰性或侵袭性/致命疾病。我们还提出，这些特征将能够预测具有不确定动力学的癌症的结果，并建议通过对中等风险前列腺癌病例的长期随访和约翰·霍普金斯大学的已知结果进行分析来测试这一点，并与哈佛大学的同事合作，进行医师健康和健康专业人员的后续研究。这项工作将共同产生高度相关的信息，可直接应用于局限性前列腺癌的临床管理。具体来说，它将产生一个区分本地化的集成签名 - 来自具有致命潜力的局部肿瘤的惰性肿瘤。此外，我们相信这些特征对于确定患有不确定动力学的前列腺癌个体的治疗策略至关重要。

 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.