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

新药物（如PARP抑制剂）的开发和批准标志着 前列腺癌的治疗尽管取得了这一进展，转移性前列腺癌仍然是一个致命的 疾病突出了发现生物标志物和开发测试的迫切需要， 及时识别前列腺癌患者，这些患者发生转移性前列腺癌的风险极高， 疾病出现之前。有了这样的测试将使临床医生能够及早治疗这些患者 来阻止疾病发展成侵袭性的形式。 拟议的研究确定了预测性生物标志物，并描述了有用的临床测试， 存在于人类基因组中。全基因组测序（WGS） 来自我们独特的前列腺癌患者队列的数据集和样本显示， 多态性L1逆转录转座子（pL 1）在转移性肝癌患者的基因组中富集， 前列腺癌，这意味着这个遗传变量是一个潜在的新的和强大的标志物， 侵袭性疾病先前的研究表明，pL 1可以通过插入突变导致癌症。 诱变我们的研究结果表明，除了先前报道的插入诱变， pL 1 s导致大的基因组缺失，使得在一些患者中存在更多的pL 1 s。 与前列腺癌进展高度相关的基因组。此外，我们还开发和 实验验证了一种新的，高通量的方法检测pL 1 s的效用， 人类DNA这种方法比WGS更灵敏，成本效益更高， 可能对数百或数千个样本进行基因组pL 1含量的病例对照研究。 利用这些发现和方法，我们假设大量的特异性pL 1 存在于前列腺癌患者基因组中的基因与前列腺癌的风险增加有关。 发展转移性疾病，因为这些元素驱动基因组不稳定性，因此， 疾病进展。我们提出了两个具体的目标，使用我们独特的队列组成， 惰性或侵袭性前列腺癌患者，可用的WGS数据集，以及我们的 新的方法来测试这一假设。Aim 1将进行病例对照研究， pL 1存在于我们队列中前列腺癌患者的基因组中。目标2将执行目标 对转移性前列腺癌中频繁突变的基因进行测序以鉴定pL 1相关的 突变和新的机制，pL 1可能有助于癌症的进展。 通过询问约400名前列腺癌患者的基因组中是否存在pL 1， 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pL 1的数量和/或组成（单独或与鉴定的 基因突变）与侵袭性前列腺癌呈正相关， 由特定基因中的pL 1引起的突变事件的频率。长期的结果 这一建议的成功将是临床上准备好的可靠的基因测试， 包括退伍军人，他们有患侵袭性前列腺癌的高风险。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。

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.