Polymorphic L1 transposons as a Genetic Variable Distinguishing Aggressive from Indolent Prostate Cancer

多态性 L1 转座子作为区分侵袭性前列腺癌和惰性前列腺癌的遗传变量

• 批准号: 10260721
• 负责人: Victoria Perepelitsa Belancio
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-12-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260721
• 关键词: APC gene; APC mutation; Age; Automobile Driving; Biological Assay; Biological Markers; Birth; Blood; Blood specimen; Breast Cancer Patient; Cancer Patient; Case-Control Studies; Clinic; Clinical; Clinical Trials; Colorectal Cancer; DNA; DNA Damage; DNA Repair Gene; Data; Data Analyses; Data Set; Defect; Detection; Development; Diagnosis; Disease; Disease Progression; Elements; Ethnic Origin; Event; Frequencies; Future; Gene Mutation; Genes; Genetic; Genetic Markers; Genome; Genomic DNA; Genomic Instability; Genomics; Goals; Health; Healthcare; Human Genome; Indolent; Inflammation; Insertional Mutagenesis; Lead; Legal patent; Link; Long Interspersed Elements; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Methodology; Methods; Mutate; Mutation; New Drug Approvals; Outcome; Outcome Study; Patient-Focused Outcomes; Patients; Prostate; Prostate Cancer therapy; Publishing; Reporting; Research Design; Retroelements; Retrotransposon; Risk; Risk Factors; Sampling; Source; Statistical Data Interpretation; Testing; Thinking; Time; Tissues; Tumor Suppressor Genes; Urology; Veterans; Vision; Work; anticancer research; base; biomarker development; biomarker discovery; cancer diagnosis; cancer type; clinically relevant; cohort; cost; cost effective; design; detection method; efficacy testing; genetic makeup; genetic testing; genome sequencing; high risk; human DNA; improved; inhibitor; invention; men; novel; novel marker; novel strategies; overtreatment; predictive marker; prospective; prospective test; prostate cancer progression; prototype; research clinical testing; success; targeted sequencing; transcriptome sequencing; tumor DNA; tumor progression; whole genome

The development and approval of new drugs (such as PARP inhibitors) marks a breakthrough in prostate cancer treatment. Despite this progress, metastatic prostate cancer remains a lethal disease highlighting a critical need for discovery of biomarkers and development of tests that can timely identify prostate cancer patients who are at highly elevated risk for developing metastatic disease before it appears. Having such a test would allow clinicians to treat these patients early to stop disease progression to its aggressive form. The proposed study identifies predictive biomarkers and describes useful clinical testing for their presence in the human genome. Our preliminary analysis of Whole Genome Sequencing (WGS) datasets and samples from our unique cohort of prostate cancer patients shows that specific polymorphic L1 retrotransposons (pL1s) are enriched in the genomes of patients with metastatic prostate cancer, meaning that this genetic variable is a potential new and powerful marker of aggressive disease. Prior work has shown that pL1s can contribute to cancer by insertional mutagenesis. Our findings show that in addition to previously reported insertional mutagenesis, pL1s cause large genomic deletions, making the presence of more pL1s in some patients' genomes highly relevant to prostate cancer progression. Furthermore, we have developed and experimentally validated the utility of a novel, high throughput method for detection of pL1s in human DNA. This method is more sensitive and cost effective than WGS, making performing a case-control study of genomic pL1 content on hundreds or thousands of samples possible. Capitalizing on these findings and methods, we hypothesize that a high number of specific pL1s present in the genomes of prostate cancer patients is associated with an increased risk of developing metastatic disease because these elements drive genomic instability and, thus, disease progression. We propose two specific aims that use our unique cohort composed of patients with either indolent or aggressive prostate cancers, available WGS datasets, and our novel methodologies to test this hypothesis. Aim 1 will perform a case-control study to identify pL1s present in genomes of prostate cancer patients in our cohort. Aim 2 will perform targeted sequencing of genes frequently mutated in metastatic prostate cancer to identify pL1-associated mutations and novel mechanisms by which pL1s may contribute to cancer progression. By interrogating the genomes of ~400 prostate cancer patients for the presence of pL1s and for mutations in genes relevant to prostate cancer, the proposed study will determine whether the number and/or composition of pL1s in patient genomes (alone or in combination with identified gene mutations) is positively associated with aggressive prostate cancer and to determine the frequency of mutagenic events cause by pL1s in specific genes. The long-term outcome of the success of this proposal will be clinically ready reliable genetic tests prospectively identifying men, including Veterans, who are at high risk of developing aggressive prostate cancer. The test could be performed using blood DNA at any time, including prior to prostate cancer diagnosis.

新药的开发和批准（例如PARP抑制剂）标志着突破 前列腺癌治疗。尽管取得了这种进展，但转移性前列腺癌仍然是致命的 疾病强调了发现生物标志物的迫切需要，并且可以开发可以 及时识别前列腺癌患者，他们的转移性风险高度升高 疾病出现之前。进行这样的测试将使临床医生能够尽早治疗这些患者 阻止疾病发展为侵略性形式。 拟议的研究确定了预测性生物标志物，并描述了其有用的临床测试 在人类基因组中的存在。我们对整个基因组测序（WGS）的初步分析 来自我们独特的前列腺癌患者队列的数据集和样品表明特定 多态L1逆转座子（PL1）富含转移性患者的基因组 前列腺癌，这意味着该遗传变量是潜在的新的强大标记 侵略性疾病。先前的工作表明，PL1可以通过插入为癌症 诱变。我们的发现表明，除了先前报道的插入诱变外， PL1会引起大型基因组缺失，使某些患者的存在更多的PL1的存在。 基因组与前列腺癌的进展高度相关。此外，我们已经开发了 实验验证了一种新型高通量方法检测PL1S中的实用性 人DNA。该方法比WGS更敏感和更具成本效益，使得执行 病例对照研究基因组PL1含量在数百或数千个样本上。 利用这些发现和方法，我们假设大量的特定PL1 存在于前列腺癌患者基因组中的 发展转移性疾病是因为这些元素促进了基因组不稳定性，因此 疾病进展。我们提出了两个使用我们独特队列的特定目标 患有懒惰或侵略性前列腺癌，可用WGS数据集的患者以及我们的 检验该假设的新方法。 AIM 1将执行案例对照研究以识别 PL1存在于我们队列中前列腺癌患者的基因组中。 AIM 2将执行针对性 在转移性前列腺癌中经常突变的基因测序以鉴定与PL1相关的 PL1可能导致癌症进展的突变和新型机制。 通过询问〜400名前列腺癌患者的基因组，以存在PL1和 与前列腺癌相关的基因突变，拟议的研究将确定是否确定 PL1在患者基因组中的数量和/或组成（单独或与已确定的 基因突变）与攻击性前列腺癌呈正相关，并确定 PL1在特定基因中引起诱变事件的频率。长期结果 该提案的成功将是临床上准备可靠的基因检测，可以识别男性， 包括患有侵略性前列腺癌的高风险的退伍军人。测试可以 可以随时使用血液DNA（包括前列腺癌诊断之前）进行。