The Impact of DNA Damage Repair Abnormalities in Prostate Cancer

DNA 损伤修复异常对前列腺癌的影响

• 批准号: 9792979
• 负责人: PHILIP W KANTOFF
• 金额: $ 192.92万
• 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/9792979
• 关键词: Address; Cancer Etiology; Cessation of life; Clinical; Clinical Investigator; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Data; Diagnosis; Disease; Early Intervention; Epidemiologist; Ethnic Origin; Ethnic group; Frequencies; Genes; Genetic Variation; Goals; Individual; Inherited; Intervention; Localized Disease; Malignant Neoplasms; Malignant neoplasm of prostate; Molecular Abnormality; Outcome; Pathogenicity; Pathologist; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Play; Prostate Cancer therapy; Protein Truncation; Research Personnel; Role; Scientist; Screening for Prostate Cancer; Series; Testing; Therapeutic; Time; United States; Variant; Vision; advanced disease; adverse outcome; base; cancer diagnosis; castration resistant prostate cancer; clinically significant; disease natural history; gene repair; high risk; improved; improved outcome; insertion/deletion mutation; men; multidisciplinary; mutational status; precision medicine; programs; prostate cancer risk; screening; systemic intervention; treatment strategy; tumor

SUMMARY/ABSTRACT Prostate cancer is the most commonly diagnosed cancer among men in the United States, with an anticipated 164,690 men being diagnosed in 2018. It is also one of the leading causes of cancer death, with approximately 29,430 deaths anticipated in 2018, usually as a result of metastatic castration-resistant prostate cancer (mCRPC). Pathogenic variants in DNA damage repair (DDR) pathway genes are prevalent in a substantial subset of men who develop mCRPC. These germline or somatic genetic abnormalities, primarily insertions and deletions resulting in protein truncations that interfere with DDR, occur in 20-25% of men with mCRPC. While several studies are underway to leverage these findings for men at the latest stages of prostate cancer, genetic variation in the DDR pathway has not yet been fully characterized for men with localized prostate cancer. While there is increasing evidence that some DDR gene aberrations may be associated with aggressive prostate cancer, this also has not been fully characterized. In the United States, where prostate cancer screening is common, over 90% of patients present initially with localized disease. It is at this point in the natural history of the disease when intervention can have the most profound impact. Thus, a major focus of this proposal is understanding the spectrum of DDR gene aberrations that promote aggressive cancers, particularly in men with high-risk localized and oligometastatic disease. Retrospective series demonstrate that DDR variants occur with low frequency in men with low-risk prostate cancer and with higher frequency in men with high-risk localized prostate cancer. This has wide-ranging clinical implications. For instance, mutational status could be used to identify those at highest risk of developing lethal prostate cancer, and therapy could be optimized based on tumor or germline findings. In addition, targeted screening could be implemented to identify those at highest risk of aggressive disease and provide an opportunity for early intervention. The overarching goal of this program is to increase our understanding of the spectrum of DDR gene aberrations that are associated with adverse outcomes in high-risk localized and oligometastatic prostate cancer. This will allow us to optimize the therapeutic approach to patients who have DDR aberrations, to detect and treat lethal disease early, and to improve outcomes for patients and their relatives who carry germline aberrations. In order to achieve our goal, we have assembled a multi-institutional and multidisciplinary group of investigators, including clinical investigators, epidemiologists, statisticians, pathologists, clinical geneticists, computational biologists, bioinformaticians, and basic scientists. Our specific aims are to determine the association between long-term clinical outcome and pathogenic germline and somatic variants in DDR genes across different ethnic groups, to develop treatment strategies for patients with germline or somatic alterations in DDR pathways, and to evaluate the functional significance of different alterations in DDR genes.

摘要/摘要 前列腺癌是美国男性中最常见的癌症，预计 164,690名男性在2018年被诊断出。这也是癌症死亡的主要原因之一，大约 2018年预计29,430例死亡，通常是由于转移性cast割前列腺癌而导致的 （MCRPC）。 DNA损伤修复（DDR）途径中的致病变异基因普遍存在 发展MCRPC的男性子集。这些种系或躯体遗传异常，主要是插入和 导致蛋白质截断的缺失会干扰DDR，其中20-25％的MCRPC男性发生。尽管 正在进行一些研究，以利用前列腺癌最新阶段的男性发现这些发现，遗传 对于局部前列腺癌的男性，DDR途径的变化尚未完全表征。尽管 有越来越多的证据表明某些DDR基因畸变可能与侵略性前列腺有关 癌症，这也没有充分表征。在美国，前列腺癌筛查是 常见的是，超过90％的患者最初出现局部疾病。正处于自然历史的这一点 当干预时，这种疾病会产生最深远的影响。因此，该提议的主要重点是 了解促进侵略性癌症的DDR基因畸变的范围，尤其是在男性中 具有高风险的局部和寡聚疾病。 回顾性系列表明，低风险前列腺男性的DDR变体以低频出现 高危局部前列腺癌男性的癌症且频率更高。这具有广泛的临床 含义。例如，突变状态可用于识别患致命的最高风险的人 可以根据肿瘤或种系发现来优化前列腺癌和治疗。另外，有针对性 可以实施筛查以识别那些患有侵略性疾病风险最高的人，并提供 早期干预的机会。 该程序的总体目标是增加我们对DDR基因谱的理解 与高风险局部和寡聚前列腺中不良结果相关的畸变 癌症。这将使我们能够优化患有DDR畸变的患者的治疗方法，以检测 并尽早治疗致命疾病，并改善携带种系的患者及其亲戚的预后 畸变。为了实现我们的目标，我们组建了一个多机构和多学科的小组 研究人员，包括临床研究者，流行病学家，统计学家，病理学家，临床遗传学家， 计算生物学家，生物信息学家和基础科学家。我们的具体目的是确定 长期临床结局与致病性种系与DDR基因中的体细胞变异之间的关联 在不同的种族中，为有种系或躯体改变的患者制定治疗策略 在DDR途径中，并评估DDR基因不同变化的功能意义。