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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

基本信息

批准号：
10495177
负责人：
KENNETH OFFIT
金额：
$ 29.41万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
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/10495177
关键词：
Accounting Address Affect African American African American population African ancestry 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 variant genomic locus high risk high risk men high risk population homologous recombination insertion/deletion mutation men mortality multi-ethnic mutational status new therapeutic target novel patient stratification patient subsets population based precision medicine prognostic prospective racial disparity therapeutic target treatment strategy tumor

项目摘要

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.

项目概要高风险、局限性前列腺癌的自然史，在 29,000 例癌症中占很大比例在美国，每年与前列腺癌相关的死亡人数变化很大：有些患者通过手术或放射治疗，而其他人则出现转移并死于疾病。迄今为止，尝试事实证明，对这些高风险、局限性前列腺癌亚群中的患者进行分层是不够的。有在非洲裔美国人群体中尤为紧迫，因为他们患致命疾病的风险最高。有一个迫切需要能够可靠地区分高危疾病中最具侵袭性的疾病形式的生物标志物。风险群体。具体来说，我们关注 DNA 损伤修复 (DDR) 途径，其中某些变异似乎与前列腺癌的侵袭性有关。在这个提案中，我们将解决两个重要问题在该领域：1）在患有高风险、局限性前列腺癌的患者中，我们能否识别出基因畸变？ DDR 通路与最具侵袭性的疾病形式相关吗？ 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？第一个目标是，我们关注 DDR 通路中的遗传种系变异。使用大型回顾和对于高风险局部前列腺癌患者的前瞻性队列，我们将对 DNA 进行测序从血液样本中提取并检查与长期致命性前列腺癌发展的关联长期随访。在我们的第二个目标中，我们将使用 DNA 探究体细胞基因组和匹配的种系来自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的关联。在第三个目标中，我们将确定更大范围内种系 DDR 的流行率。非裔美国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为该协会提供无与伦比的视角 DDR 与致死性前列腺癌之间的关系。我们有潜力 i) 发现特定的种系和致命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 抑制或针对 DDR 的铂化疗等策略途径； ii) 发现可开发为最具攻击性的筛选工具的种系生物标志物前列腺癌的形式； iii) 定义 DDR 通路基因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位点和目标基因以及其他项目将激发治疗干预的新目标。