Project 1: Molecular Predictors of Prostate Cancer Progression and Mortality

项目摘要/摘要 前列腺癌(PC)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) 筛查是有争议的，目前对高危男性的考虑也是不够的。另外， 临床病理标准不足以区分惰性疾病和侵袭性疾病。最近的 在转移性PC中发现高到中等外显率的种系癌症风险突变的高发 (MPC)将导致增加对未受影响的男性亲属的基因检测和级联检测，从而确定 男性患攻击性个人电脑的风险很高。初步证据表明，精炼癌症的必要性 在这一高危人群中进行筛查。这个项目的总体意图是寻找具有生殖系突变的男性 兴趣，无论是那些患有MPC的人，以及他们的男性一级亲属，他们都是侵略性PC的高危人群。 我们试图通过评估进一步在生殖系DNA修复基因(GDRG)缺陷的背景下表征PC 临床、病理和分子特征，包括有针对性的下一代测序方法；招募 通过级联基因检测获得高危男性一级亲属；并提供一种新的PC早期检测临床 纳入新生物标志物的试验，包括年龄调整的PSA阈值、成像、新的尿液生物标志物 和我们在过去的赠款期间发现和验证的肿瘤预后生物标记物，并进一步 了解为获得最佳结果所需的级联基因测试的关键过程。这个 建议的目标是： 具体目标1：确定gDRG突变携带者的临床、病理和分子预测因素 在患有MPC的男性中。 具体目的2：对MPC高危男性gDRG突变携带者进行早期检测研究。 具体目标3：描述从首发病例到首发病例的逐步级联基因检测过程 风险一级亲属(FDR)。 这一努力建立在我们目前以人口为基础的孢子工作基础上，重点是寻找和验证小说 侵袭性PC的预后生物标记物(例如，肿瘤DNA甲基化和mRNA表达生物标记物 区分转移进展和特定于PC的死亡率的高危男性)和向 更直接的临床适用性。我们相信，我们的方法将引起男性的高度兴趣和相关性 MPC和gDRG以及他们的儿子和兄弟，他们可能因为携带MPC而增加患MPC的风险 GDRG突变。目前，对于患PC风险较高的男性，尚无统一的PC早期检测建议 由遗传性gDRG突变定义。我们的PC早期检测临床研究将使用已建立的和新的 微创生物标记物，目标是改变这一高危群体的护理标准。

PROJECT SUMMARY/ABSTRACT Prostate cancer (PC) is a major cause of cancer-related morbidity and mortality. Prostate-specific antigen (PSA) screening is controversial, and current consideration of high-risk men is inadequate. Additionally, clinicopathological criteria are insufficient to differentiate indolent versus aggressive disease. The recent discovery of a high prevalence of high-to-moderate penetrance germline cancer risk mutations in metastatic PC (mPC) will lead to increased genetic testing and cascade testing of unaffected male relatives, thus identifying men at high risk for developing aggressive PC. Preliminary evidence suggests the need for refined cancer screening in this high-risk group. The overall intent of this project is to find men with germline mutations of interest, both those with mPC as well as their male first-degree relatives who are at high risk for aggressive PC. We seek to further characterize PC in the context of germline DNA repair gene (gDRG) defects using evaluation of clinical, pathologic and molecular features, including targeted next generation sequencing methods; to recruit at-risk male first-degree relatives through cascade genetic testing; and to offer a novel PC early detection clinical trial incorporating novel biomarkers, including age-adjusted PSA thresholds, imaging, novel urine biomarkers and the tumor prognostic biomarkers we discovered and validated in the past grant period, and to further understand the crucial process of cascade genetic testing that will be required for optimal outcomes. The proposed aims are: Specific Aim 1: Determine clinical, pathologic and molecular predictors of gDRG mutation carriers among men with mPC. Specific Aim 2: Conduct an early detection study for male gDRG mutation carriers at high risk for mPC. Specific Aim 3: Characterize the stepwise cascade genetic testing process from index cases to their at risk first-degree relatives (FDRs). This effort builds upon our current population-based SPORE work focused on finding and validating novel prognostic biomarkers for aggressive PC (e.g., tumor DNA methylation and mRNA expression biomarkers for distinguishing men at high risk for metastatic progression and PC-specific mortality) and transitions towards a more direct clinical applicability. We believe our approach will be of high interest and relevance to men with mPC and gDRG, and their sons and brothers who may be at increased risk for mPC due to carrying the same gDRG mutation. At present, no unified PC early detection recommendations exist for men at increased PC risk defined by inherited gDRG mutations. Our PC early detection clinical study will use established and novel minimally invasive biomarkers with a goal of changing the standard of care for this high-risk group.