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

多基因风险分层结合 mpMRI 来识别临床相关的前列腺癌

• 批准号: 10610626
• 负责人: ADAM S KIBEL
• 金额: $ 54万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-12 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610626
• 关键词: Address; Age; Age Years; Algorithms; Artificial Intelligence; Biological Markers; Biopsy; Black race; Cancer Etiology; Cessation of life; Clinical; DNA Repair; Data; Diagnosis; Disease; Early Diagnosis; Ensure; Evaluation; General Population; Genetic; Genetic Risk; Genotype; Gleason Grade for Prostate Cancer; Goals; Heritability; Hospitals; Human; Image; Incidence; Inherited; Institution; Knowledge; Lesion; Life; MRI Scans; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Medical center; Military Personnel; National Cancer Institute; Pathway interactions; Patients; Population; Populations at Risk; Primary Care; Prophylactic treatment; Prospective cohort; Public Health Schools; Resources; Risk; Role; Screening for Prostate Cancer; Serial Magnetic Resonance Imaging; Single Nucleotide Polymorphism; Testing; Time; Translating; Translations; United States; United States National Institutes of Health; Universities; University Hospitals; Variant; Woman; Work; age group; age stratification; artificial intelligence algorithm; biobank; black men; clinical center; clinical practice; clinical risk; clinically relevant; clinically significant; cohort; deep learning; disorder risk; evidence based guidelines; follow-up; gene repair; genetic information; genetic testing; genetic variant; genome wide association study; high risk; high risk men; improved; learning strategy; man; men; mortality; multi-ethnic; novel; overtreatment; patient population; polygenic risk score; population based; premalignant; programs; prospective; prostate cancer prevention; prostate cancer risk; racial disparity; racial diversity; radiologist; rare variant; recruit; risk prediction; risk stratification; screening; serial imaging; stem; tool; trial design; tumor; wasting

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.

前列腺癌对任何癌症的遗传力估计最高，前列腺变异性的58％ 癌症的发生率归因于遗传因素。基因组广泛的关联研究已验证269 与前列腺癌风险密切相关的单核苷酸多态性。我们发现一个 将这些SNP结合的多民族多基因风险评分（PR）表现出9倍的风险差异 疾病比较黑人和白人男性的男性与低PR的男性。该建议旨在翻译 该前列腺癌PR通过解决四个重要问题：1）PR可以是 与其他工具集成在DNA损伤修复（DDR）途径中的其他工具，包括 早期检测策略的一部分，以鉴定与临床上的，潜在的致命前列腺癌？ 2）在什么 男人一生中的指向如果他的遗传风险增加，他应该开始早期发现计划吗？ 3）什么是 成像的最佳间隔以检测具有高遗传风险的男性临床相关癌症？ 该协作U01提案以三个具体目标解决了这些问题。目标1-我们将前景 确定与MRI集成的前列腺癌PR鉴定高级，可能致命的能力 前列腺癌。我们将从MGB Biobank，Walter Reed招募1500名男子（600个黑色，900名白色） 生物库，以及霍华德大学和杨百翰及妇女医院的初级保健网络。所有人都会 根据基因分型分为低，平均和高风险。 PSA，MRI和DDR变体将是 获得升高的PSA或异常MRI的活检。我们希望找到PRS确定 患有前列腺癌风险的人群，而DDR变体和MRI识别具有临床相关的子集 疾病。在AIM 2中，我们将评估MRI在临床上有用的男人生活中的什么时候。我们的人口会 从40-69岁的5岁年龄段进行成像。此外，没有癌症的男性处于高遗传风险 将以2年间隔在NCI上进行串行MRI成像。在AIM 3中，我们将确定是否深度学习 应用于mpMRI并通过遗传风险告知的方法可以更准确地预测重要的癌症。 这将是现场预期试验中的第一个将种系遗传学与MRI融合的人，以识别有风险的男性 临床上的前列腺癌。结果将通过建立最佳的早期来产生短期影响 检测算法并显示将种系上的信息纳入早期检测的实用性 战略。它将确定MRI在遗传较高的患者中检测临床相关的癌症中的作用 风险。长期目标是利用所获得的知识来设计高危人群的试验 更长的后续措施证明基因检测可以提高我们预防前列腺癌死亡率的能力 通过靶向筛查和预防。重要的是，患有临床意义疾病风险较低的男性可能 保留筛查，预防和治疗。这些信息可以直接转化为患者 人群。该提案的另一个优势是包括种族多样化的患者人群。