Molecular Predictors of Prostate Cancer Progression and Mortality

前列腺癌(PCa)是男性最常见的实体肿瘤，也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)检测增加了被诊断为前列腺癌的男性人数，但这些患者中约30-42%的患者患有惰性肿瘤，进展为临床上有意义的前列腺癌的可能性很低。仅凭临床病理标准并不总是足以预测哪些肿瘤将保持惰性而不是变得具有侵袭性，因此许多患者被过度治疗，有些患者治疗不足。因此，迫切需要生物标记物来区分患有更少和更具侵袭性疾病的男性。 遗传变异(如SNPs)和肿瘤表观基因组异常(如DNA高甲基化)都可能导致PCa的侵袭性。初步证据支持这两种机制，它们可能改变宿主-肿瘤免疫、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转化为临床使用的侵袭性前列腺癌的遗传表观遗传生物标记物。为了实现这一目标，该项目有以下目标： 1)完成对两个独立的PCa患者队列中30个PCSM相关SNP的小组的验证； 2)研究前列腺癌组织全基因组DNA甲基化(450K CpG位点)与前列腺癌特异性结局(如复发、转移、PCSM)的关系； 3)检测PCSM相关SNPs(Aim 1)和顶级差异甲基化基因(Aim 2)作为一组综合的预后生物标志物，用于区分临床局限性侵袭性PCa。 拟议的计划建立在我们之前的孢子工作基础上，利用了基于群体的PCA队列，包括生殖系DNA、肿瘤组织、临床和PCA特有的结果数据，以及其他拥有可用DNA和结果数据的PCA队列。将完成单变量、分层和多变量分析，以评估PCSM相关SNPs和与侵袭性PCa相关的顶级差异甲基化基因的潜在临床实用价值。将使用COX比例风险模型来计算风险比、95%顺式系数和p值，以检查个体和生殖系遗传和体细胞(DNA甲基化)生物标记物的组合与PCa结果的关联。总的目标是识别和验证预后遗传-表观遗传生物标记物，这将转化为更好的患者管理和结果，以及识别新的分子靶点，可能导致新的治疗或预防前列腺癌的方法。

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 under-treated. 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.