(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-允许某些个体在其他高致命性癌症的预期限制之外存活？”胰腺癌是癌症死亡的第四大原因，近年来生存率几乎没有改善。在过去的二十年中，我们作为胰腺癌治疗的领先中心的经验描述了这种疾病的病理生物学和手术创新，使得治疗性切除具有长期生存率。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。我们现在在这个提议中引入了胰腺癌遗传学和表观遗传学的领导者以及临床医生和病理学家的合作，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，各种研究已经揭示了肿瘤侵袭性与基因表达特征之间的关系，特别是与干细胞模式相关的基因表达特征，并且新出现的证据表明这具有重要的表观遗传成分。对于胰腺癌的这种概念基础，我们所知甚少。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特征，可以用来开发可以治愈胰腺癌的新疗法。我们已经在我们的数据集中确定了300名胰腺腺癌患者的队列，他们是长期幸存者，称为VLTS。在Aim 1中，我们将使用下一代测序（NGS）的组合来未知地鉴定全基因组中的基因表达和表观遗传差异，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甲基化和染色质修饰。在第二个目标中，我们将进行生物信息学分析，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。我们的合作者正在对该队列进行外显子组测序的信息将被整合。最后，在第三个目标中，这些信息将被翻译成一种预后特征，可以在我们的3000名患者的大型注释数据集中进行验证。在这个方案中，我们有机会接触到合适的患者队列，以及经验丰富的团队来了解和剖析导致这些癌症致死率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的生存曲线。

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.