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

(PQD3)与胰腺癌长期生存相关的分子谱

• 批准号: 8687225
• 负责人: Nita Ahuja
• 金额: $ 45.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2018-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687225
• 关键词: Address; Automobile Driving; Awareness; Base Sequence; Behavioral; Bioinformatics; Biological; Biological Assay; Biological Markers; Cancer Etiology; Cancer Patient; Cessation of life; ChIP-seq; Chromatin; Clinical; Collaborations; DNA Methylation; Data Set; Development; Disease; Epigenetic Process; Evaluation; Event; Excision; Future; Gene Expression; Gene Expression Profile; Genetic; Genome; Individual; Knowledge; Long-Term Survivors; Malignant Neoplasms; Malignant neoplasm of pancreas; Maps; Methods; Methylation; Molecular Profiling; Mutation; Neoplasm Metastasis; Nodal; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathologist; Pathology; Pathway interactions; Patients; Pattern; Prognostic Marker; Research Personnel; Role; Sampling; Scientist; Stem cells; Surgeon; Technology; The Cancer Genome Atlas; Therapy Clinical Trials; Thick; Translating; United States; base; cancer genetics; chromatin modification; cohort; exome sequencing; experience; improved; innovation; insight; next generation sequencing; novel; novel therapeutics; outcome forecast; prognostic; programs; public health relevance; tumor

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.

项目概要/摘要： 在此应用中，我们建议解决 PQD3：“潜在的因果事件是什么 - 例如， 遗传、表观遗传、生物、行为或环境——允许某些个体生存 超出了其他高致死性癌症的预期极限？”胰腺癌是第四大癌症 近年来，癌症死亡的主要原因，生存率改善甚微。我们的 作为胰腺癌治疗领先中心的经验描述了胰腺癌的病理学 这种疾病和手术创新使得治愈性切除术能够在患者中实现长期生存。 过去二十年。与此同时，我们的中心定义了表观遗传学和遗传的作用 癌症的改变并将这些知识转化为正在进行的治疗试验。我们现在带来 在该提案中，胰腺癌遗传学和表观遗传学领域的领导者进行了合作 与临床医生和病理学家一起了解长期幸存者的特征 这种通常致命的恶性肿瘤。最近，多项研究揭示了两者之间的关系 肿瘤侵袭性和基因表达特征，特别是与干细胞模式相关， 新出现的证据表明，这具有重要的表观遗传成分。很少的是 了解胰腺癌的此类概念基础。我们的假设是，长期 胰腺癌足月幸存者具有独特的基因表达和表观遗传 可用于开发治愈胰腺的新疗法的特征 癌症。我们在我们的研究中心内确定了一个由 300 名胰腺癌患者组成的队列 非常长期幸存者的数据集，称为 VLTS。在目标 1 中，我们将使用组合 下一代测序 (NGS) 来不确定地识别基因表达和表观遗传 整个基因组的差异，以及使用基于阵列的技术广泛 与其他 VLTS 患者相比，描述了这些 VLTS 患者的 DNA 甲基化和染色质修饰特征 快速进展者 (RP) 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联系起来并进行剖析 驱动 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。终于在 第三个目标，这些信息将被转化为开发一个可以预测的特征 在我们包含 3000 名患者的注释齐全的大型数据集中得到了验证。在这个提案中，我们可以访问 向正确的患者群体以及经验丰富的团队提供帮助，以了解和剖析 遗传和表观遗传程序驱动这些癌症的致死性或惰性，并将其转化为 这些知识可以改变胰腺癌的生存曲线。