Molecular Predictors of Prostate Cancer Progression and Mortality

前列腺癌（PCa）是男性最常见的实体瘤，是癌症相关发病率和死亡率的主要原因。前列腺特异性抗原（PSA）测试增加了被诊断患有PCa的男性的数量，但是这些患者中约30 - 42%具有惰性肿瘤，其进展为临床显著PCa的可能性低。临床病理学标准本身并不总是足以预测哪些肿瘤将保持惰性或变得具有侵袭性，因此许多患者被过度治疗，有些患者治疗不足。因此，迫切需要生物标志物来区分患有侵袭性疾病较少与更具侵袭性疾病的男性。两种遗传变异（例如，SNP）和肿瘤表观基因组畸变（例如，DNA超甲基化）可能有助于PCa的侵袭性。初步证据支持这两种机制，这可能会改变宿主肿瘤免疫力，肿瘤生长速度或转移倾向。这项人口科学研究的总体目的是验证可以转化为临床使用的侵袭性PCa的遗传-表观遗传生物标志物。为了实现这一目标，该项目具有以下目标：1）在两个独立的PCa患者队列中完成一组30个PCSM相关SNP的验证; 2）表征前列腺肿瘤组织中与PCa特异性结果相关的全基因组DNA甲基化（450 K CpG位点）谱（例如，复发、转移、PCSM）;以及3）测试经验证的PCSM相关SNP（Aim 1）和排名靠前的差异甲基化基因（Aim 2）作为用于区分临床局部侵袭性PCa的预后生物标志物的综合组。 拟议的计划建立在我们之前的SPORE工作的基础上，利用了基于人群的PCa队列，包括生殖系DNA、肿瘤组织、临床和PCa特异性结局数据，以及其他具有可用DNA和结局数据的PCa队列。将完成单变量、分层和多变量分析，以评价PCSM相关SNP和与侵袭性PCa相关的排名靠前的差异甲基化基因的潜在临床效用。将使用考克斯比例风险模型计算风险比、95% CI和p值，以检查生殖系遗传和体细胞（DNA甲基化）生物标志物的个体和组合与PCa结局的相关性。总体目标是确定和验证预后遗传-表观遗传生物标志物，这些生物标志物将转化为更好的患者管理和结局，并确定可能导致PCa新疗法或预防方法的新分子靶点。

Prostate cancer (PCa) is the most common solid tumor in men and is a major cause of cancer-related morbidity and mortality. Prostate-specific antigen (PSA) testing has increased the number of men diagnosed with PCa, but -30-42% of these patients have indolent tumors that carry a low probability for progression to clinically significant PCa. Clinicopathological criteria alone are not always adequate for predicting which tumors will remain indolent vs become aggressive, so many patients are over-treated and some are undertreated. Thus, biomarkers to distinguish men with less vs more aggressive disease are urgently needed. Both inherited genetic variation (e.g., SNPs) and tumor epigenomic aberrations (e.g., DNA hypermethylation) likely contribute to PCa aggressiveness. Preliminary evidence supports both mechanisms, which may alter host-tumor immunity, tumor growth rate, or metastatic propensity. The overall intent of this population sciences research is to validate genetic-epigenetic biomarkers for aggressive PCa that can be translated into clinical use. Toward this goal, the project has the following aims: 1) To complete validation of a panel of 30 PCSM-associated SNPs in two independent PCa patient cohorts; 2) To characterize genome-wide DNA methylation (450K CpG sites) profiles in prostate tumor tissue in association with PCa-specific outcomes (e.g., recurrence, metastasis, PCSM); and, 3) To test validated PCSM-associated SNPs (Aim 1) and top-ranked differentially methylated genes (Aim 2) as an integrated panel of prognostic biomarkers for distinguishing clinically localized aggressive PCa. The proposed plan builds on our prior SPORE work, taking advantage of a population-based PCa cohort with germline DNA, tumor tissue, clinical and PCa-specific outcomes data, as well as other PCa cohorts with available DNA and outcomes data. Univariate, stratified, and multivariate analyses will be completed to evaluate PCSM-associated SNPs and top-ranked differentially methylated genes associated with aggressive PCa for potential clinical utility. The Cox proportional hazards model will be used to calculate hazard ratios, 95% CIs, and p-values to examine the association of individual and combinations of germline genetic and somatic (DNA methylation) biomarkers with PCa outcomes. The overall goal is to identify and validate prognostic genetic-epigenetic biomarkers that will translate into better patient management and outcomes as well as to identify new molecular targets that may lead to novel therapies or prevention approaches for PCa.