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（如PARP抑制剂）的研发和批准标志着该领域的突破 前列腺癌治疗。尽管取得了这一进展，转移性前列腺癌仍然是致命的癌症 疾病凸显了发现生物标志物和开发能够检测的测试的迫切需要 及时识别发生转移风险较高的前列腺癌患者 疾病出现之前。进行这样的测试将使临床医生能够及早治疗这些患者 阻止疾病进展至侵袭性形式。 拟议的研究确定了预测性生物标志物并描述了对其进行有用的临床测试 存在于人类基因组中。我们对全基因组测序（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本表明，特定的 多态性 L1 逆转录转座子 (pL1s) 在转移性癌症患者的基因组中富集 前列腺癌，这意味着该遗传变量是潜在的新的强大标志物 侵袭性疾病。先前的工作表明 pL1 可以通过插入促进癌症 诱变。我们的研究结果表明，除了之前报道的插入突变外， pL1 导致大量基因组缺失，使得一些患者体内存在更多 pL1 基因组与前列腺癌进展高度相关。此外，我们还开发并 实验验证了一种新颖的高通量方法在检测 pL1 中的实用性 人类DNA。该方法比 WGS 更灵敏且更具成本效益，使得执行 可以对数百或数千个样本进行基因组 pL1 含量的病例对照研究。 利用这些发现和方法，我们假设大量特定的 pL1 存在于前列腺癌患者基因组中的基因与患前列腺癌的风险增加有关 发展为转移性疾病，因为这些因素会导致基因组不稳定，因此， 疾病进展。我们提出了两个具体目标，利用我们独特的群体组成： 患有惰性或侵袭性前列腺癌的患者、可用的 WGS 数据集以及我们的 检验这一假设的新方法。目标 1 将进行病例对照研究以确定 pL1 存在于我们队列中前列腺癌患者的基因组中。目标2将执行有针对性的 对转移性前列腺癌中经常突变的基因进行测序，以确定 pL1 相关的 pL1 可能导致癌症进展的突变和新机制。 通过询问约 400 名前列腺癌患者的基因组中是否存在 pL1 以及 与前列腺癌相关的基因突变，拟议的研究将确定是否 患者基因组中 pL1 的数量和/或组成（单独或与已识别的组合） 基因突变）与侵袭性前列腺癌呈正相关，并确定 特定基因中 pL1 引起的诱变事件的频率。的长期成果 该提案的成功将为临床做好准备，进行可靠的基因测试，前瞻性地识别男性， 包括退伍军人，他们患侵袭性前列腺癌的风险很高。测试可以 可以随时使用血液 DNA 进行，包括在前列腺癌诊断之前。