The Impact of DNA Damage Repair Abnormalities in Prostate Cancer

总结/摘要 前列腺癌是美国男性中最常见的诊断癌症， 2018年有164，690名男性被确诊。它也是癌症死亡的主要原因之一，大约 预计2018年将有29，430人死亡，通常是由于转移性去势抵抗性前列腺癌 （mCRPC）。DNA损伤修复（DDR）途径基因的致病性变体在大量的哺乳动物中普遍存在。 发生mCRPC的男性亚组。这些生殖系或体细胞遗传异常，主要是插入和 导致干扰DDR的蛋白质截短的缺失发生在20 - 25%的mCRPC男性中。而 一些研究正在进行中，以利用这些发现为男性在前列腺癌的最新阶段，遗传 对于患有局限性前列腺癌的男性，DDR途径的变异还没有被完全表征。而 越来越多的证据表明，某些DDR基因畸变可能与侵袭性前列腺相关， 癌症，这也没有得到充分的表征。在美国，前列腺癌筛查是 常见的是，超过90%的患者最初表现为局部疾病。在自然历史的这个阶段， 当干预能够产生最深远的影响时，因此，本提案的一个主要重点是 了解DDR基因畸变的频谱，促进侵袭性癌症，特别是在男性中 高风险的局限性和寡转移性疾病。 回顾性研究表明，DDR变异在低风险前列腺患者中发生率较低。 癌症，并且在患有高风险局限性前列腺癌的男性中具有更高的频率。这具有广泛的临床意义。 影响例如，突变状态可以用来识别那些发展致命疾病的风险最高的人。 前列腺癌，并且可以基于肿瘤或生殖系发现来优化治疗。此外，针对 可以进行筛查，以确定那些侵袭性疾病风险最高的人， 早期干预的机会。 该计划的总体目标是增加我们对DDR基因谱的了解， 与高危局限性和少转移性前列腺不良结局相关的畸变 癌这将使我们能够优化DDR畸变患者的治疗方法， 早期治疗致命疾病，改善携带生殖细胞的患者及其亲属的预后， 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小组， 研究者，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。我们的具体目标是确定 DDR基因的致病性生殖系和体细胞变异与长期临床结果的关系 在不同的种族群体中，为生殖细胞或体细胞改变的患者制定治疗策略， 在DDR途径，并评估DDR基因的不同改变的功能意义。

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.