Polygenic risk stratification combined with mpMRI to identify clinically relevant prostate cancer

前列腺癌在所有癌症中具有最高的遗传率估计值，前列腺癌的变异性为58 癌症发病率归因于遗传基因因素。全基因组关联研究已经验证了269 单核苷酸多态性与前列腺癌风险密切相关。我们发现一个 结合这些SNP的多种族多基因风险评分（PRS）显示， 在黑人和白色男性中比较高PRS与低PRS的男性。该提案旨在翻译 通过解决四个重要问题，将前列腺癌PRS纳入临床实践：1）PRS可以 与其他工具集成，包括MRI和DNA损伤修复（DDR）途径中的罕见遗传变异， 早期检测策略的一部分，以确定临床相关的，潜在的致命性前列腺癌？2)在什么 如果一个人的遗传风险增加，他的生命中是否应该开始早期检测计划？3)是什么 在高遗传风险的男性中检测临床相关癌症的最佳成像间隔？ U 01的这一合作提案在三个具体目标中解决了这些问题。目标1 -我们将前瞻性 确定结合MRI的前列腺癌PRS识别更高级别、潜在致命性的能力 前列腺癌我们将从MGB生物库沃尔特里德招募1500人（600名黑人，900名白色） 生物银行，以及霍华德大学和布里格姆妇女医院的初级保健网络。所有的男人都会 根据基因分型分为低风险、中风险和高风险。PSA、MRI和DDR变体将 随后活检PSA升高或MRI异常。我们希望找到PRS识别一个 DDR变体和MRI确定了具有临床相关性的子集， 疾病在目标2中，我们将评估MRI在男性生命中的临床有用性。本港人口 在40-69岁的5岁年龄组进行成像。此外，没有癌症的高遗传风险男性 将每隔2年在NCI接受一系列MRI成像。在目标3中，我们将确定深度学习是否 应用于mpMRI和遗传风险的方法可以更准确地预测重大癌症。 这将是第一个将生殖系遗传学与MRI相结合的前瞻性临床试验，以确定男性的风险， 临床相关的前列腺癌。结果将通过建立一个最佳的早期 检测算法，并显示了将生殖系信息纳入早期检测的实用性 战略它将确立MRI在检测高遗传易感性人群中临床相关癌症中的作用。 风险长期目标将是利用获得的知识来设计风险人群的试验， 更长的随访，以证明基因检测可以提高我们预防前列腺癌死亡率的能力 通过有针对性的筛查和预防。重要的是，患有临床显著疾病的低风险男性可以 避免筛查、预防和治疗。这些信息可以直接转化为患者 人口。该提案的另一个优点是纳入了种族多样化的患者人群。

Prostate cancer has the highest estimate of heritability of any cancer, with 58% of variability in prostate cancer incidence attributed to inherited genetic factors. Genome wide association studies have validated 269 single nucleotide polymorphisms that are strongly associated with prostate cancer risk. We found that a multiethnic polygenic risk score (PRS) combining these SNPs demonstrate a 9-fold difference in risk of disease comparing men with high vs. low PRS in a both Black and White men. This proposal aims to translate this prostate cancer PRS into clinical practice by addressing four important questions: 1) Can the PRS be integrated with other tools including MRI and rare genetic variants in DNA damage repair (DDR) pathways as part of an early detection strategy to identify clinically-relevant, potentially lethal prostate cancer? 2) At what point in a man's life should an early detection program begin if he is at increased genetic risk? 3) What is the optimal interval of imaging to detect clinically relevant cancer in men at high genetic risk? This collaborative U01 proposal addresses these issues in three specific aims. Aim 1 - we will prospectively determine the ability of a prostate cancer PRS integrated with MRI to identify higher-grade, potentially lethal prostate cancer. We will recruit 1500 men (600 Black, 900 White) from the MGB Biobank, the Walter Reed Biobank, and the primary care network at Howard University and Brigham & Women's Hospital. All men will be stratified into low, average, and high risk on the basis genotyping. PSA, MRI, and DDR variants will be obtained followed by biopsy for elevated PSA or abnormal MRI. We expect to find the PRS identifies a population at risk for prostate cancer while the DDR variants and MRI identifies a subset with clinically relevant disease. In Aim 2, we will evaluate at what point in a man's life an MRI is clinically useful. Our population will be imaged across 5 year age groups from 40-69 years. In addition, men at the high genetic risk without cancer will undergo serial MRI imaging at the NCI at 2 year intervals. In Aim 3 we will determine if deep learning methods applied to mpMRI and informed by genetic risk can more accurately predict significant cancers. This will be the first in field prospective trial to integrate germline genetics with MRI to identify men at risk of clinically-relevant prostate cancer. The results will have short-term impact by establishing an optimal early detection algorithm and show the utility of incorporating information on the germline into an early detection strategy. It will establish the role of MRI in detecting clinically relevant cancers among those with high genetic risk. The longer-term goal will be to use the knowledge gained to design trials of the at-risk populations with longer follow-up to prove that genetic testing can improve our ability to prevent prostate cancer mortality through targeted screening and prophylaxis. Importantly, men at low risk for clinically significant disease could be spared screening, prophylaxis and treatment. This information can be directly translated into patient populations. An additional strength of this proposal is the inclusion in racially diverse patient populations.