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

描述(由申请人提供)：在本申请中，我们建议解决PQD3：“哪些潜在的因果事件--例如，遗传、表观遗传、生物、行为或环境--允许某些人在其他高致命性癌症的预期极限之外存活下来？”胰腺癌是癌症死亡的第四大原因，近年来存活率几乎没有改善。我们作为领先的胰腺癌治疗中心的经验勾勒出了这种疾病的病理生物学，在过去的20年里，外科技术的创新使根治性切除得以长期存活。与此同时，我们的中心已经定义了表观遗传学和基因改变在癌症中的作用，并将这些知识转化为正在进行的治疗试验。我们现在将胰腺癌遗传学和表观遗传学领域的领军人物与临床医生和病理学家一起纳入这项提案，以了解这种通常致命的恶性肿瘤的长期幸存者的特征。最近，各种研究揭示了肿瘤侵袭性和基因表达特征之间的关系，特别是与干细胞模式有关的关系，新出现的证据表明，这具有重要的表观遗传学成分。人们对胰腺癌的这种概念基础知之甚少。我们的假设是，胰腺癌的长期幸存者具有独特的基因表达和表观遗传学特征，可以利用这些特征来开发治愈胰腺癌的新疗法。在我们的数据集中，我们已经确定了300名胰腺癌患者的队列，他们是非常长期的幸存者，被称为VLT。在目标1中，我们将使用下一代测序(NGS)的组合来识别整个基因组中的基因表达和表观遗传学差异，并使用基于阵列的技术来广泛表征这些VLTS患者与快速进展(RP)的胰腺癌患者的DNA甲基化和染色质修改。在第二个目标中，我们将进行生物信息学分析，以将表观遗传变化与表达变化联系起来，并剖析驱动VLTS和RP患者不同临床命运的主要途径。我们的合作者正在进行的外显子组测序中的信息将被整合。最后，在第三个目标中，这些信息将被翻译成一个预后信号，可以在我们3000名患者的大型注释良好的数据集中得到验证。在这项提案中，我们可以与经验丰富的团队一起接触到合适的患者队列，以了解和剖析导致这些癌症致命性或惰性的遗传和表观遗传程序，并将这些知识转化为改变胰腺癌生存曲线的知识。

DESCRIPTION (provided by applicant): 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.