The Impact of DNA Damage Repair Abnormalities in Prostate Cancer

摘要/摘要 前列腺癌是美国男性中最常见的被诊断出的癌症，预计 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，大约有 预计2018年将有29,430人死亡，通常是转移性去势抵抗前列腺癌的结果 (MCRPC)。DNA损伤修复(DDR)途径基因中的致病变异在 患有mCRPC的男性的一部分。这些生殖系或体细胞遗传异常，主要是插入和 导致蛋白质截断干扰DDR的缺失发生在20%-25%的男性mCRPC患者中。而当 几项研究正在进行中，以利用这些发现在前列腺癌的最新阶段，基因 对于患有局限性前列腺癌的男性来说，DDR途径的变异还没有得到充分的表征。而当 越来越多的证据表明，一些DDR基因异常可能与侵袭性前列腺癌有关 癌症，这一点也没有得到充分的定性。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限性疾病。这是在自然历史的这一点上 对疾病进行干预时可以产生最深刻的影响。因此，这项提案的一个主要焦点是 了解促进侵袭性癌症的DDR基因异常的频谱，特别是在男性 有高风险的局限性和少转移性疾病。 回顾系列研究表明，DDR变异在低风险前列腺癌患者中出现的频率很低 癌症，在高危局限性前列腺癌的男性中发病率较高。这有广泛的临床应用 这意味着什么。例如，突变状态可以用来识别那些具有最高致命性风险的人。 前列腺癌，治疗可以根据肿瘤或生殖细胞的发现进行优化。此外，有针对性的 可以实施筛查来识别那些侵袭性疾病风险最高的人，并提供 提供早期干预的机会。 这个项目的主要目标是增加我们对DDR基因谱的了解 与高危局部性和少转移性前列腺癌的不良结局相关的异常 癌症。这将使我们能够优化对有DDR异常的患者的治疗方法，以检测 及早治疗致命疾病，并改善携带生殖系的患者及其亲属的预后 像差。为了实现我们的目标，我们召集了一个多机构和多学科的小组 调查人员，包括临床调查人员、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基因的致病种系和体细胞变异与长期临床结局的关系 跨不同种族，为生殖系或躯体改变患者制定治疗策略 并评价DDR基因不同突变的功能意义。

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.