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

项目1：项目总结 主动监测(AS)是前列腺癌(PC)患者避免过度治疗的重要选择，但 需要更好的生物标记物来避免推荐给可能患有侵袭性疾病的人。 AS的基本原理是，14%的男性被诊断为PC，其中约80%有临床上的局限性疾病， 80%的人接受早期治疗，但只有3%的人最终死于PC。因为治疗可能会有副作用，就像 另一种可能减少过度治疗的选择。对低风险PC患者进行监测，并进行治疗 通常在患者退出AS时推荐使用。然而，在10年内，高达60%的男性 退出AS协议。然而，大多数不合格的患者在临床上都没有得到诊断- 重大疾病从一开始，而不是疾病“进展”从低到高。此外, 许多接受明确治疗的患者是因为“PSA焦虑症”。事实上，20%-40%的AS 患者最终被发现患有临床上重要的疾病，延迟诊断的影响仍然存在。 待定。在延迟治疗后，高达50%的患者PSA复发。其中一些人 发展为PC的转移和死亡。PC有很强的遗传成分，全基因组关联研究 现已发现与PC风险相关的&gt；100个单核苷酸多态(SNPs) 解释了35%的遗传风险。一些PC风险SNP也与PC攻击性有关， 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 失败了。具体地说，这项提议解决了这样的假设：1)当候选人携带生殖系变异时 与AS衰竭相关；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 与PC相关的变异也会影响失败；以及3)低风险男性生殖系变异的知识 PC可能会影响治疗决定。我们的初步研究检验了候选生殖系变异与 PC在一大组男性中注册，作为协议使用最新的SNP和整个外显子组阵列技术。 我们建议的研究利用孢子遗传学的资源，并作为工作组和非孢子 作为研究人员以及许多在这一领域工作的非孢子调查人员。具体目标1将涉及统计 对基因分型数据进行分析。特定目标2将以队列的形式独立地验证这些变异。特定的 AIM 3将在电子计算机方法中使用，以尽可能地在细胞信号通路上映射经过验证的变体 此外，还需要对相关基因进行功能分析。将制定特定目标4 识别更有可能失败的男性的算法。这项工作将具有翻译意义，最终将导致 为了1)用于筛选和治疗决策的新的生物标志物，2)识别参与的信号通路(S) 侵袭性疾病，3)确定新治疗和可能的PC预防的药物靶点，以及 4)提高对影响PC攻击性的遗传因素的认识。

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.