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

基本信息

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
项目类别：
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

项目摘要

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.

前列腺癌的遗传力估计是所有癌症中最高的，前列腺癌的变异性为 58% 癌症的发生与遗传因素有关。第 269 章与前列腺癌风险密切相关的单核苷酸多态性。我们发现一个结合这些 SNP 的多种族多基因风险评分 (PRS) 表明，以下风险存在 9 倍的差异：比较黑人和白人中 PRS 高与低的疾病。该提案旨在翻译通过解决四个重要问题，将前列腺癌 PRS 引入临床实践：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，例如识别临床相关的、可能致命的前列腺癌的早期检测策略的一部分？ 2）什么时候如果一个人的遗传风险增加，是否应该在他生命中的某个时刻开始早期检测计划？ 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？ U01 的这项合作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 PRS 与 MRI 相结合的能力，以识别更高等级、可能致命的癌症前列腺癌。我们将从 MGB 生物库 Walter Reed 招募 1500 名男子（600 名黑人，900 名白人）生物银行以及霍华德大学和布莱根妇女医院的初级保健网络。所有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 变体将随后进行活检以发现 PSA 升高或 MRI 异常。我们期望找到 PRS 来识别有患前列腺癌风险的人群，而 DDR 变异和 MRI 识别出具有临床相关性的子集疾病。在目标 2 中，我们将评估 MRI 在男性生命的哪个阶段具有临床用途。我们的人民将对 40 至 69 岁的 5 岁年龄组进行成像。此外，没有患癌症的高遗传风险男性将每隔 2 年在 NCI 进行连续 MRI 成像。在目标 3 中，我们将确定深度学习是否应用于 mpMRI 并根据遗传风险提供信息的方法可以更准确地预测重大癌症。这将是第一个将种系遗传学与 MRI 相结合的现场前瞻性试验，以识别存在以下风险的男性：临床相关的前列腺癌。通过建立最佳的早期效果，结果将产生短期影响检测算法并展示将种系信息纳入早期检测的实用性战略。它将确立 MRI 在检测高遗传基因患者中临床相关癌症方面的作用风险。长期目标是利用所获得的知识来设计针对高危人群的试验更长时间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，患有临床重大疾病的低风险男性可以免于筛查、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不同种族的患者群体。