Impact of Germline Genetic Variants and Failure of Active Surveillance for Prostate Cancer

项目1：项目概要 积极监测（AS）是前列腺癌（PC）患者避免过度治疗的重要选择，但 需要更好的生物标志物来避免将AS推荐给可能患有侵袭性疾病的人。 AS的基本原理是PC在14%的男性中被诊断，其中约80%具有临床局限性疾病， > 80%接受早期治疗，但最终只有约3%死于PC。由于治疗可能有副作用，AS是 这是一个可以减少过度治疗的替代方案。对低风险PC男性进行监测， 通常在患者从AS中退出时推荐。然而，在10年内，高达60%的男性 退出AS协议。然而，大多数"AS失败"的患者在临床上未被诊断- 从一开始就是严重的疾病，而不是从低级别“进展”到高级别的疾病。此外，本发明还提供了一种方法， 许多进行确定性治疗的患者是因为"PSA焦虑"。事实上，20 - 40%的AS 患者最终被发现患有临床上显著的疾病，并且延迟诊断的影响仍然存在 有待确定。延迟治疗后，高达50%的患者PSA复发。其中一些人 发生转移并死于前列腺癌。PC具有很强的遗传成分，与全基因组关联研究 （GWAS）现在已经确定了> 100个与PC风险相关的单核苷酸多态性（SNP）， 解释> 35%的遗传风险。一些PC风险SNP也与PC攻击性相关， 但结果并不一致。我们的目标是通过研究生殖系遗传变异和AS来澄清这些结果。 失败具体而言，该提案解决了以下假设：1）AS候选人携带生殖系变异 与AS失败相关; 2）使用更高密度的SNP和外显子组阵列进行基因分型将使我们能够识别 也影响AS失败的PC相关变异;和3）低风险男性生殖系变异的知识 PC可能会影响治疗决策。我们的初步研究检查了候选种系变异相关的 与PC在一个大集合的男性登记在AS协议使用最新的SNP和全外显子组阵列技术。 我们提出的研究利用了孢子遗传学和AS工作组的资源， AS研究以及许多在这一领域工作的非SPORE研究人员。具体目标1将需要统计 基因分型数据的分析。具体目标2将在独立AS队列中验证这些变体。具体 aim 3将尽可能使用计算机模拟方法来绘制细胞信号传导途径上的验证变体 药物靶点，也将需要相关基因的功能分析。具体目标4将制定 算法来识别更有可能失败的男性。这项工作将产生转化的影响，最终导致 1）用于筛选和治疗决策的新生物标志物，2）鉴定参与 侵袭性疾病，3）鉴定用于新治疗和可能的PC预防的药物靶标，以及 4)推进我们对影响PC攻击性的遗传因素的理解。

PROJECT 1: PROJECT SUMMARY Active surveillance (AS) is an important option for prostate cancer (PC) patients to avoid overtreatment, but better biomarkers are needed to avoid recommending AS to someone who may harbor aggressive disease. The rationale for AS is that PC is diagnosed in 14% of men, of whom ~80% have clinically localized disease, >80% undergo early treatment, but only ~3% ultimately die of PC. As treatment may have side effects, AS is an alternative option that may reduce overtreatment. Men with low-risk PC are monitored, and treatment is usually recommended when the patient withdraws from AS. However, within 10 years, up to ~60% of men withdraw from AS protocols. However, the majority of patients who “fail AS” have undiagnosed clinically- significant disease from the beginning rather than disease that “progresses” from low to high grade. In addition, many of the patients who go on definitive therapy do so because of “PSA anxiety.” In fact, 20-40% of AS patients are eventually found to have clinically significant disease, and the impact of delayed diagnosis remains to be determined. After delayed treatment up to 50% of patients have PSA recurrence. Some of these men develop metastases and die of PC. PC has a strong genetic component, and genome-wide association studies (GWAS) have now identified >100 single nucleotide polymorphisms (SNPs) associated with PC risk, together explaining >35% of the inherited risk. Some PC risk SNPs also have been associated with PC aggressiveness, but results have been inconsistent. We aim to clarify such results by studying germline genetic variants and AS failure. Specifically, this proposal addresses the hypotheses that: 1) AS candidates carry germline variants associated with AS failure; 2) genotyping with higher-density SNP and exome arrays will allow us to identify PC-associated variants that also impact AS failure; and 3) knowledge of germline variants in men with low-risk PC may affect treatment decisions. Our preliminary studies examine candidate germline variants associated with PC in a large set of men enrolled in AS protocols using the latest SNP and whole exome array technology. Our proposed studies leverage resources of the SPORE Genetics and AS working groups and non-SPORE AS studies as well as many non-SPORE investigators working in this field. Specific aim 1 will entail statistical analyses of the genotyping data. Specific aim 2 will validate these variants in independent AS cohorts. Specific aim 3 will use in silico approaches to map validated variants on cell signaling pathways as possible pharmaceutical targets and also will entail functional analyses of the relevant genes. Specific aim 4 will develop algorithms to identify men more likely to fail AS. This work will have translational implications, ultimately leading to 1) new biomarkers for screening and treatment decisions, 2) identifying the signaling pathway(s) involved in aggressive disease, 3) identifying pharmaceutical targets for new treatments and possibly PC prevention, and 4) advancing our understanding of genetic factors that influence PC aggressiveness.