Genetic Predictors of Prostate Cancer Survival

前列腺癌生存的遗传预测因素

• 批准号: 10580599
• 负责人: ROBERT J. KLEIN
• 金额: $ 68.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580599
• 关键词: Address; Adverse event; Biochemical; Biological Markers; Biology; Biopsy; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Clinic; Clinical; Code; Data; Diagnosis; Disease; Disease Progression; Distant Metastasis; Early Diagnosis; Genes; Genetic; Genetic Determinism; Genetic study; Genomic approach; Genomics; Hematopoietic Neoplasms; Heritability; Hospitals; Image; Impairment; Indolent; Inherited; Kininogenase; Knowledge; Length; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Modeling; Mutation; PF4 Gene; PSA screening; Pathway interactions; Play; Price; Prognostic Factor; Prostate; Prostate Cancer therapy; Quality of life; Recurrence; Reflex action; Risk; Role; Screening for Prostate Cancer; Screening procedure; Signal Transduction; Single Nucleotide Polymorphism; Testing; Time; Transcription Alteration; Translating; Twin Studies; United States; Variant; Work; biomarker panel; cancer diagnosis; cancer survival; clinical risk; clinical translation; clinically significant; cohort; cost; exome sequencing; follow-up; genetic information; genetic predictors; genetic risk factor; genetic testing; genetic variant; genome wide association study; high risk; high risk men; improved; insight; kallikrein 4; men; middle age; model design; novel; peripheral blood; population based; predictive marker; prostate cancer progression; rare variant; risk stratification; screening; trait; transcriptome; unnecessary treatment

Project Summary / Abstract Even though most men diagnosed with prostate cancer will not die of the disease, prostate cancer is still the second leading cause of cancer death among men in the United States. While screening for prostate cancer reduces death from disease, this comes at the price of both unnecessary biopsies that reveal no evidence of cancer and treatment of otherwise indolent cancer resulting in unnecessary adverse events. Therefore, there is an unmet need for improved screening tools for prostate cancer. To address this need, we have previously developed a four-kallikrein biomarker panel that is now commercially available as a reflex test for use after an initial PSA screening; found that the four kallikrein model improves the prediction, prior to any diagnosis of prostate cancer, of which men may die of prostate cancer; and identified SNPs associated with survival time after diagnosis, independent of known prognostic factors. Combining these SNPs and the four kallikrein panel improves our ability to identify men at risk of dying from prostate cancer even further. Based on these findings, we propose here a germline genomic approach to identify men at risk of dying from prostate cancer. By leveraging recent computational advances in genomic analysis, we will take a gene-centered approach to identify genes for which genetically controlled transcriptional alterations and/or functional coding mutations influence survival time in prostate cancer. Using these genes, along with known genetic risk factors for prostate cancer and the four kallikrein panel, we will build and test models designed to identify men at risk for clinically significant prostate cancer in order to better stratify men in the screening context prior to biopsy. Specifically, we will: 1) Identify genes for which genetically controlled expression level changes and/or rare coding variants alter the risk of dying from prostate cancer; 2) Determine at what stage(s) of disease progression these genetic changes operate; and 3) Improve our 4-kallikrein biomarker predictor of lethal prostate cancer through incorporation of genetic data. This will be achieved by conducting both a transcriptome-wide association study (TWAS) with prostate specific models and a whole exome sequencing study in a set of well-annotated cohorts with long follow-up time after prostate cancer diagnosis. Successful completion of these aims will enable better risk stratification of men prior to prostate cancer diagnosis. We envision these findings being useful in the screening context, enabling more precise identification of men at high risk of dying from prostate cancer in the next two decades, thereby reducing death from prostate cancer due to the benefits of early detection while avoiding unnecessary biopsies and unneeded treatment of otherwise indolent cancers. Furthermore, these findings will be useful in understanding the biology of lethal prostate cancer as we anticipate these findings will pinpoint new genes and pathways that play important roles in prostate cancer progression.

项目概要/摘要 尽管大多数被诊断患有前列腺癌的男性不会死于该病，但前列腺癌仍然是最常见的癌症。 美国男性癌症死亡的第二大原因。在筛查前列腺癌时 减少因疾病造成的死亡，这是以两次不必要的活检为代价的，这些活检没有发现任何证据 癌症和其他惰性癌症的治疗会导致不必要的不​​良事件。因此，有 对改进前列腺癌筛查工具的需求尚未得到满足。为了满足这个需求，我们之前 开发了一种四激肽释放酶生物标志物组，现已上市，可作为反射测试，供在 初始 PSA 筛查；发现四种激肽释放酶模型可以在任何诊断之前改善预测 前列腺癌，男性可能死于前列腺癌；并确定了与生存时间相关的 SNP 诊断后，独立于已知的预后因素。将这些 SNP 和四个激肽释放酶组合结合起来 进一步提高我们识别有死于前列腺癌风险的男性的能力。基于这些发现， 我们在这里提出一种种系基因组方法来识别有死于前列腺癌风险的男性。经过 利用基因组分析方面最新的计算进展，我们将采取以基因为中心的方法 识别基因控制转录改变和/或功能编码突变的基因 影响前列腺癌的生存时间。使用这些基因以及已知的前列腺遗传风险因素 癌症和四种激肽释放酶组，我们将建立和测试模型，旨在识别有临床风险的男性 显着的前列腺癌，以便在活检前的筛查背景下更好地对男性进行分层。具体来说， 我们将： 1) 识别基因控制表达水平变化和/或罕见编码变异的基因 改变死于前列腺癌的风险； 2) 确定这些遗传因素处于疾病进展的哪个阶段 变更操作； 3) 通过以下方式改进我们的致命性前列腺癌的 4-激肽释放酶生物标志物预测因子 纳入遗传数据。这将通过进行全转录组关联研究来实现 （TWAS）在一组注释良好的队列中使用前列腺特异性模型和全外显子组测序研究 前列腺癌诊断后需要较长的随访时间。成功完成这些目标将使 在前列腺癌诊断之前对男性进行更好的风险分层。我们预计这些发现将有助于 筛查背景，能够更准确地识别死于前列腺癌的高风险男性 未来二十年，由于早期检测的好处，从而减少前列腺癌的死亡，同时 避免对惰性癌症进行不必要的活检和不必要的治疗。此外，这些 研究结果将有助于了解致命性前列腺癌的生物学，因为我们预计这些发现将 查明在前列腺癌进展中发挥重要作用的新基因和途径。