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管理中有几个关键的未满足的需求。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行性和潜在致命的癌症。为了解决这一关键需求，我们首先提出进行整合的多维基因组，表观基因组和表达分析，以揭示表征惰性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乳腺癌切除术中被器官限制的Gleason评分为6（或更低）的筛查检测（例如PSA筛查）病变。我们认为这些肿瘤是惰性的，因为它们似乎没有转移的能力。相比之下，我们将Gleason评分8-10的肿瘤等同于“间隔期”或症状性肿瘤，因为即使采用初次治疗，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局的其他人群来验证本项目中发现的关键标志物/途径。我们假设，我们的多模态基于基因组的综合方法，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，因此我们将同时全面描述非裔美国人前列腺癌的特征，以揭示导致结局种族差异的分子特征。我们将验证使用具有确定结局的大型病例队列获得的特征，包括：（1）约翰霍普金斯主动监测队列和（2）来自BLSA（巴尔的摩老龄化纵向研究）的前列腺癌病例，BLSA是一项自1954年以来随访的观察性男性队列，尸检记录为惰性或侵袭性/致死性疾病。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，并建议通过分析具有长期随访和已知结果的中度风险前列腺癌病例来测试这一点，这些病例来自约翰霍普金斯，并与来自哈佛的同事合作，来自医生的健康和健康专业人员的随访研究。这项工作将产生高度相关的信息，可以直接应用于局部前列腺癌的临床管理。具体地说，它将产生一个综合的签名，区分本地化的- 惰性肿瘤从具有致死潜力的局部肿瘤。此外，我们相信这些特征将是决定治疗策略的个人与前列腺癌的不确定动力学的关键。

 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.