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

项目总结 自然病史的高危、局限性前列腺癌，在29,000人中占很大比例 在美国，每年与前列腺癌相关的死亡人数是高度可变的：有患者可以通过治疗治愈 手术或放射治疗，而其他人则发生转移并死于他们的疾病。到目前为止，试图 事实证明，在这些高危、局限性前列腺癌的亚组中对患者进行分层是不够的。的确有 在非洲裔美国人中尤其紧迫，因为他们患致命疾病的风险最高。有一个 对生物标记物的巨大需求，这种生物标记物可以可靠地区分高危人群中最具侵略性的疾病 风险群体。具体地说，我们关注的是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。在这项提案中，我们将解决两个重要问题 在这一领域：1)在高危、局限性前列腺癌患者中，我们能否识别出 DDR途径与最具侵袭性的疾病形式有关？2)DDR变异是否有助于 非洲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途径中的遗传生殖系变体。使用大型回顾和 高危、局限性前列腺癌患者的预期队列，我们将进行DNA测序 从血液样本中提取，并研究与长期致命性前列腺癌发生的相关性。 学期随访。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 从根治性前列腺切除标本和相应的血液样本中提取，我们将研究 与致命性疾病有关。在第三个目标中，我们将在更大的范围内确定生殖系DDR的流行率 非洲裔美国人前列腺癌患者的队列，并估计DDR突变的贡献程度 前列腺癌的差异。 完成这项提案中概述的实验将提供一个无与伦比的视角来了解这种联系 DDR和致命形式的前列腺癌之间的关系。我们有潜力i)发现特定的生殖系并 致命疾病的体细胞生物标记物，可用于确定当时的治疗策略 诊断，可能使用PARP抑制或针对DDR的铂类化疗 途径；二)发现生殖系生物标记物，可开发为最具攻击性的筛查工具 前列腺癌的形式；以及iii)定义DDR途径基因的突变可以解释的程度 前列腺癌的种族差异。组成该数据集的遗传基因座和目标基因以及 其他项目将刺激治疗干预的新目标。

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.