The Clinical and Epidemiological Characterization of Pathogenic DNA Damage Repair Pathway Variation in Prostate Cancer

前列腺癌致病性 DNA 损伤修复途径变异的临床和流行病学特征

• 批准号: 9792980
• 负责人: KENNETH OFFIT
• 金额: $ 43.22万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9792980
• 关键词: Accounting; Address; Affect; African; African American; American; BRCA2 gene; Biological; Biological Markers; Blood specimen; CHEK2 gene; Cancer Patient; Cessation of life; Clinical; Cohort Analysis; DNA; DNA Repair; DNA Repair Pathway; DNA analysis; Dana-Farber Cancer Institute; Data; Data Set; Development; Diagnosis; Disease; Epidemiology; European; Event; Follow-Up Studies; Frequencies; Genes; Genetic; Genetic Screening; Genome; Health; Health Professional; Hospitals; Inherited; International; Localized Disease; Longterm Follow-up; Malignant neoplasm of prostate; Memorial Sloan-Kettering Cancer Center; Mutation; Natural History; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; PARP inhibition; PTEN gene; Pathogenicity; Pathway interactions; Patient Care; Patients; Physicians; Platinum; Population; Population Study; Populations at Risk; Prevalence; Prospective cohort; Prostatic Neoplasms; Protein Truncation; Public Health Schools; Radiation; Radical Prostatectomy; Reproducibility; Retrospective cohort; Risk; Role; Sampling; Screening for Prostate Cancer; Screening procedure; Specimen; TMPRSS2 gene; TP53 gene; Therapeutic Intervention; Time; Treatment Protocols; Variant; Vision; base; cancer health disparity; castration resistant prostate cancer; chemotherapy; clinical risk; cohort; deep sequencing; disorder risk; experimental study; first-in-human; gene repair; genetic profiling; genetic variant; high risk; high risk men; high risk population; homologous recombination; insertion/deletion mutation; men; mortality; mutational status; new therapeutic target; novel; patient stratification; patient subsets; population based; precision medicine; prognostic; prospective; racial disparity; therapeutic target; treatment strategy; tumor

PROJECT SUMMARY The natural history of high-risk, localized prostate cancer, accounting for a substantial proportion of the 29,000 prostate cancer–related deaths per year in the U.S., is highly variable: there are patients who are cured with surgery or radiation, while others develop metastases and succumb to their disease. To date, attempts to stratify patients within these subsets of high-risk, localized prostate cancer have proven inadequate. There is particular urgency within the African American population, where risk of lethal disease is highest. There is a tremendous need for biomarkers that can reliably distinguish the most aggressive forms of disease within high- risk groups. Specifically, we focus on the DNA damage repair (DDR) pathway, where certain variants appear to be associated with prostate cancer aggressiveness. In this proposal, we will address two important questions in the field: 1) Among patients with high-risk, localized prostate cancer, can we identify genetic aberrations in DDR pathway associated with the most aggressive forms of the disease? 2) Do DDR variants contribute to increased risk of aggressive prostate cancer among African American men? In the first aim, we focus on inherited germline variants in the DDR pathway. Using large retrospective and prospective cohorts of patients with high-risk, localized prostate cancer, we will perform sequencing in DNA derived from blood samples and examine associations with development of lethal prostate cancer over long- term follow-up. In our second aim, we will interrogate the somatic genome and matched germline using DNA derived from radical prostatectomy specimens and corresponding blood samples, and we will study associations with lethal disease. In the third aim, we will determine the prevalence of germline DDR in a larger cohort of African American prostate cancer patients and estimate the extent to which DDR mutations contribute to prostate cancer disparities. Completion of the experiments outlined in this proposal will provide an unparalleled look at the association between DDR and lethal forms of prostate cancer. We have the potential to i) discover specific germline and somatic biomarkers for lethal disease that could be used to determine treatment strategies at the time of diagnosis, perhaps using strategies such as PARP inhibition or platinum chemotherapy that target the DDR pathway; ii) discover germline biomarkers that could be developed as screening tools for the most aggressive forms of prostate cancer; and iii) define the extent to which mutations in in DDR pathway genes may explain racial disparities in prostate cancer. The genetic loci and target genes comprising this dataset together with the other projects will stimulate new targets for therapeutic intervention.

项目摘要 自然史高危、局限性前列腺癌占29000例的相当比例 前列腺癌相关的死亡人数，是高度可变的：有些病人是治愈的， 手术或放射治疗，而其他人发展为转移并死于他们的疾病。迄今为止， 在这些高危、局限性前列腺癌亚群中对患者进行分层已被证明是不够的。有 非洲裔美国人群体中的特别紧迫性，致命疾病的风险最高。有一个 对生物标志物的巨大需求，这些生物标志物可以可靠地区分高血压中最具侵袭性的疾病形式， 风险群体。具体来说，我们专注于DNA损伤修复（DDR）途径，其中某些变体似乎 与前列腺癌的侵袭性有关。在本提案中，我们将解决两个重要问题 在该领域：1）在高危、局限性前列腺癌患者中，我们能否识别出遗传畸变 DDR通路与最具侵袭性的疾病形式有关？2)DDR变体是否有助于 非裔美国男性患侵袭性前列腺癌的风险增加？ 在第一个目标中，我们专注于DDR途径中的遗传性种系变异。使用大型回顾性和 前瞻性队列的高风险，局限性前列腺癌患者，我们将进行DNA测序， 从血液样本中提取，并检查与长期致命前列腺癌发展的相关性， 长期随访。在我们的第二个目标中，我们将使用DNA询问体细胞基因组和匹配的种系 来源于根治性前列腺切除术标本和相应的血液样本，我们将研究 与致命疾病有关。在第三个目标中，我们将在一个更大的群体中确定生殖系DDR的患病率。 非裔美国人前列腺癌患者队列，并估计DDR突变的贡献程度 前列腺癌的差异。 完成本提案中概述的实验将提供对该协会的无与伦比的了解 DDR和致命的前列腺癌之间的联系我们有潜力i）发现特定的种系， 致死性疾病的体细胞生物标志物，可用于确定治疗策略， 诊断，可能使用PARP抑制或靶向DDR的铂化疗等策略 ii）发现生殖系生物标志物，可以开发为最具侵略性的筛选工具， 形式的前列腺癌;和iii）定义DDR途径基因中的突变可以解释的程度 前列腺癌的种族差异构成该数据集的遗传基因座和靶基因与 其他项目将刺激治疗干预的新目标。