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.

前列腺癌的遗传率是所有癌症中最高的，有58%的变异性。 癌症的发生归因于遗传因素。全基因组关联研究已经证实了269 与前列腺癌风险密切相关的单核苷酸多态。我们发现一个 结合这些SNPs的多种族多基因风险评分(Prs)显示，患糖尿病的风险相差9倍。 在黑人和白人男性中，比较高RPS和低RPS的男性。这项提案旨在将 通过解决四个重要问题将前列腺癌PR投入临床实践：1)PR能否 与其他工具集成，包括核磁共振和DNA损伤修复(DDR)途径中的罕见遗传变异，如 早期发现策略的一部分，以识别临床相关的、潜在致命的前列腺癌？2)在什么部位 如果一个人的遗传风险增加，他应该开始早期检测计划吗？3)什么是 在高遗传风险男性中检测临床相关癌症的最佳成像间隔？ 这份协作性的U01提案通过三个具体目标解决了这些问题。目标1-我们将前瞻性地 确定前列腺癌PR与MRI相结合识别高级别、潜在致命性疾病的能力 前列腺癌。我们将从MGB生物库招募1500人(600名黑人，900名白人)，沃尔特·里德 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 根据基因分型将风险分为低风险、中等风险和高风险。PSA、MRI和DDR变体将是 PSA升高或MRI异常后进行活检。我们预计将发现PR识别出一个 当DDR变异体和MRI确定与临床相关的子集时，前列腺癌高危人群 疾病。在目标2中，我们将评估一个人一生中的哪个时间点核磁共振在临床上是有用的。我们的人口将 从40岁到69岁的5个年龄段进行成像。此外，没有癌症的高遗传风险男性 将每隔两年在NCI接受一次系列MRI成像。在目标3中，我们将确定深度学习 将方法应用于mpMRI，并了解遗传风险，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核磁共振相结合的现场前瞻性试验，以确定男性患癌症的风险。 与临床相关的前列腺癌。通过建立一个最优的早期计划，结果将产生短期影响 检测算法，并展示了将生殖系信息合并到早期检测中的有效性 策略。这将确定核磁共振在检测高基因人群中临床相关癌症方面的作用。 风险。较长期的目标将是使用获得的知识来设计高危人群的试验 更长时间的随访，以证明基因测试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，临床重大疾病风险较低的男性可能 免去筛查、预防和治疗。这些信息可以直接转化为患者 人口。这项提议的另一个优势是将其纳入种族多样化的患者群体。