(PQD3)Molecular Profiles associated with Long-Term Survival in pancreas Cancer

项目摘要/摘要： 在本申请中，我们建议解决PQD3：“什么是潜在的因果事件--例如， 遗传的、表观遗传的、生物的、行为的或环境的--允许某些个体存活下来 超出其他高致命性癌症的预期极限？“胰腺癌是第四位。 是癌症死亡的主要原因，近年来存活率几乎没有改善。我们的 作为领先的胰腺癌治疗中心的经验勾勒出了胰腺癌的病理生物学 这种疾病和外科技术的创新使得根治性切除能够长期存活在 过去的二十年。与此同时，我们的中心已经定义了表观遗传学和遗传学的作用 并将这些知识转化为正在进行的治疗试验。我们现在带来的是 在这项提案中，胰腺癌遗传学和表观遗传学领域的领军人物合作 与临床医生和病理学家一起了解长期幸存者的签名 这种通常致命的恶性肿瘤。最近，各种研究揭开了两者之间的关系 肿瘤侵袭性和基因表达特征，特别是与干细胞模式有关的特征， 新出现的证据表明，这有一个重要的表观遗传学成分。很少有 已知胰腺癌的这种概念基础。我们的假设是- 胰腺癌的长期幸存者有独特的基因表达和表观遗传学 可用于开发治愈胰腺的新疗法的签名 癌症。我们已经确定了300名胰腺癌患者在我们的 长期存活的数据集，称为VLT。在目标1中，我们将使用组合 下一代测序(NGS)以不可知的方式识别基因表达和表观遗传学 整个基因组的差异以及使用基于阵列的技术来广泛 这些VLTS患者的DNA甲基化和染色质修饰的特征与 快速进展(RP)的胰腺癌患者。在第二个目标中，我们将执行 生物信息学分析将表观遗传变化与表达变化相关联并解剖 决定VLTS和RP患者不同临床命运的主要途径。信息 我们的合作者正在进行的外显子组测序将被整合在一起。终于来了 第三个目标是，这些信息将被翻译成一个预测性的签名，可以 在我们3000名患者的大型注释良好的数据集中进行了验证。在这份提案中，我们可以访问 与有经验的团队一起对合适的患者队列进行了解和解剖 基因和表观遗传程序驱动这些癌症的致命性或惰性并翻译 这样的知识可以改变胰腺癌的生存曲线。

PROJECT SUMMARY/ABSTRACT: In this application, we propose to address PQD3: "What underlying causal events - e.g., genetic, epigenetic, biologic, behavioral, or environmental - allow certain individuals to survive beyond the expected limits of otherwise highly lethal cancers?" Pancreas cancer is the fourth leading cause of cancer death with minimal improvements in survival in recent years. Our experience as the leading center in treatment of pancreas cancer delineated the pathobiology of this disease and surgical innovations allowed curative resections with long term survival in the past two decades. Concomitantly our center has defined the role of epigenetics and genetic alterations in cancer and translated this knowledge for ongoing therapeutic trials. We now bring within this proposal a collaboration of leaders in pancreas cancer genetics and epigenetics along with clinicians and pathologists to understand the signature of long-term survivors from this generally lethal malignancy. Various studies, recently, have unraveled the relation between tumor aggressiveness and gene expression signatures, especially related to stem cell patterns, and emerging evidence indicates that this has an important epigenetic component. Very little is known about such conceptual underpinnings in pancreas cancer. Our hypothesis is that long- term survivors from pancreas cancer have a unique gene expression and epigenetic signature that can be leveraged to develop novel therapies that can cure pancreas cancer. We have identified a cohort of 300 patients with pancreas adenocarcinomas within our dataset who are Very Long-Term Survivors, termed VLTS. In Aim 1, we will use a combination of next generation sequencing (NGS) to agnostically identify gene expression and epigenetic differences in the whole genome, as well as use array-based technologies to extensively characterize DNA methylation and chromatin modifications in these VLTS patients compared to pancreas cancer patients who are Rapid Progressors (RP). In the second Aim, we will perform bioinformatics analyses to correlate the epigenetic changes to expression changes and dissect the major pathways that drive the different clinical fates of VLTS and RP patients. Information from ongoing exome sequencing on this cohort by our collaborators will be integrated. Finally in the third Aim, this information will be translated to develop a prognostic signature that can be validated in our large well-annotated dataset of 3000 patients. In this proposal, we have access to the right cohort of patients along with the experienced teams to understand and dissect the genetic and epigenetic programs driving lethality or indolence in these cancers and translate such knowledge to change the survival curve in pancreas cancer.