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

描述（由申请人提供）：在本申请中，我们提出解决PQD 3：“什么潜在的因果事件-例如，遗传的、表观遗传的、生物的、行为的或环境的--允许某些个体生存超过否则高度致命的癌症的预期极限？“胰腺癌是癌症死亡的第四大原因，近年来生存率的改善微乎其微。我们作为胰腺癌治疗的领先中心的经验描绘了这种疾病的病理生物学和手术创新允许在过去二十年中长期生存的根治性切除术。与此同时，我们的中心已经确定了表观遗传学和遗传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的领导者沿着临床医生和病理学家合作，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特征，可以利用这些特征来开发可以治愈胰腺癌的新疗法。我们在我们的数据集中确定了300例胰腺癌患者，他们是非常长期的生存者，称为VLTS。在目标1中，我们将使用下一代测序（NGS）的组合来不可知地鉴定全基因组中的基因表达和表观遗传差异，以及使用基于阵列的技术来广泛表征与快速进展（RP）的胰腺癌患者相比，这些VLTS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，以将表观遗传变化与表达变化相关联，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的信息将被整合。最后，在第三个目标中，将这些信息转化为可以在我们的3000名患者的大型注释数据集中验证的预后特征。在这项提案中，我们有机会与经验丰富的团队一起沿着进入正确的患者队列，以了解和剖析这些癌症中驱动致死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.