Mitochondria, MicroRNA, and Metabolites in Predicting Aggressive Prostate Cancer

项目概要（项目4） 由于常规PSA筛查，前列腺癌越来越多地在早期阶段被发现，导致5年 存活率接近100%。然而，许多筛查检测到的前列腺癌是无痛的，但约90% 的局限性前列腺癌男性接受前期积极治疗， 发病率。相反，一些患有潜在侵袭性前列腺癌的患者， 干预可以选择延迟治疗。这种过度治疗和治疗不足的困境， 急性，适用于临床定义的中等风险患者。仅临床变量不足以 准确区分侵袭性疾病和惰性疾病。迫切需要生物标志物来细化风险 分层在这个项目中，我们将重点关注三个有前途的生物标志物：线粒体DNA，microRNA， 代谢物。这些多功能和相互关联的分子与肥胖有关， 前列腺癌的症状有哪些利用美国两个最大的前列腺癌患者队列， 该项目将对这些生物标志物与临床变量进行综合分析， 侵袭性前列腺癌我们将在诊断时使用从比较极端表型中获得的知识 （高风险前列腺癌与低风险前列腺癌），以更好地对临床定义的 中等风险状况。有四个具体目标：1）确定新的遗传易感因素， 前列腺癌的症状我们将使用三阶段设计：发现、内部复制和 外部验证这一目标的患者总数将为4，200人（3，000名白人和1，200名非洲人）， 美国人[AA]）。我们设计了一个包含约20，000个单核苷酸多态性（SNP）的定制阵列， 包括miRNA调控途径中的SNP，mtDNA中的SNP，以及肥胖和前列腺癌， 易感SNP。2)为了鉴定新的中间生物标志物，包括线粒体DNA拷贝数， 外周血白细胞DNA、循环miRNA和循环代谢物作为侵袭性乳腺癌的预测因子 前列腺癌的诊断我们将再次使用三阶段设计。3)为了检验 在特殊患者人群中验证的生物标志物，包括GS 7患者，接受 乳腺癌切除术或放疗，以及MD安德森主动监测研究中招募的特殊人群。 4)构建多变量预后列线图，包括流行病学危险因素，临床变量， 和生物标志物。我们将完善临床变量来预测GS患者的预后 7例，局限性患者行直肠癌切除术或放疗。我们将比较预测的准确性 我们的列线图与现有的仅基于临床变量的列线图的比较。

PROJECT SUMMARY (Project 4) Prostate cancer is increasingly detected at early stages due to routine PSA screening, leading to a 5-year survival rate of nearly 100%. However, many screening-detected prostate cancer are indolent, yet about 90% of men with localized prostate cancer receive upfront aggressive treatments that often cause significant morbidity. Conversely, some patients with potentially aggressive prostate cancer who would benefit from early intervention may choose to delay treatment. This dilemma of overtreatment and undertreatment is particularly acute for patients with clinically defined intermediate risk. Clinical variables alone are not sufficient to accurately differentiate aggressive and indolent diseases. Biomarkers are urgently needed to refine risk stratification. In this project, we will focus on three promising biomarkers: mitochondrial DNA, microRNA, and metabolites. These multi-functional and interconnected molecules are related to obesity, an established risk factor to aggressive prostate cancer. Leveraging two of the largest prostate cancer patient cohorts in the U.S., this project will perform integrative analyses of these biomarkers with clinical variables to more precisely define aggressive prostate cancer. We will use knowledge gained from comparing extreme phenotypes at diagnosis (high-risk prostate cancer versus low-risk prostate cancer) to better stratify patients with clinically defined intermediate risk profiles. There are four specific aims: 1) To identify novel genetic susceptibility factors for aggressive prostate cancer at diagnosis. We will use a three-phase design: discovery, internal replication, and external validation. The total number of patients in this aim will be 4,200 (3,000 whites and 1,200 African- Americans [AA]). We have designed a custom array of about 20,000 single-nucleotide polymorphisms (SNPs), which include SNPs in miRNA regulatory pathways, SNPs in mtDNA, and obesity- and prostate cancer- predisposing SNPs. 2) To identify novel intermediate biomarkers, including the mtDNA copy number in peripheral blood leukocyte DNA, circulating miRNAs, and circulating metabolites as predictors of aggressive prostate cancer at diagnosis. We will again use a three-phase design. 3) To test the prognostic value of validated biomarkers in special patient populations, including GS 7 patients, localized patients receiving prostatectomy or radiotherapy, and a special population enrolled in an MD Anderson active surveillance study. 4) To construct multivariate prognostic nomograms that include epidemiological risk factors, clinical variables, and biomarkers from this project. We will refine clinical variables in predicting the prognosis in patients with GS of 7 and in localized patients receiving prostatectomy or radiotherapy. We will compare the predictive accuracy of our nomograms with existing ones that are based solely on clinical variables.