DNA Methylation and gene expression variations influence pituitary adenoma hormonal function and invasive growth

项目摘要：DNA甲基化和基因表达变异对垂体腺瘤的影响 激素功能与侵袭性生长 脑垂体腺瘤(PAS)是最常见的颅内肿瘤之一，可引起 甲状旁腺功能减退症、神经功能障碍和致命性激素过度分泌障碍，如库欣病 疾病和肢端肥大症。虽然通常是良性的，但PA侵袭周围的硬脑膜、骨和脑 在近一半有症状的患者中很明显，是实现长期肿瘤的主要障碍 控制、荷尔蒙缓解和患者生存正常化。基因突变并不是主要原因 在非家族性帕金森综合症的发展或行为中的作用，并且存在着重大的知识差距 了解PA激素功能和侵袭性生长的分子基础。或者， 已知表观遗传(如DNA甲基化)和基因表达变化会影响PA 表型，但这些影响因基因位置和背景而异。我们的团队表演了第一个 表观基因组范围的初步研究，以探索DNA甲基化和基因表达与 PA的行为，并验证了几个与PA激素功能和侵袭有关的基因。使用 类似的工作流程，我们的总体目标是定义DNA甲基化和基因表达在 根据PA激素亚型和侵袭性对PA激素分泌和侵袭进行分层的一项较大研究 入侵状态。我们假设：1)DNA甲基化和表达的变异与 亚型特异的PA激素功能和侵袭性；2)DNA甲基化和表达数据可以 用于识别新的分子定义的PA类别并补充当前的PA诊断方案； 3)受调控的目的基因优先表达将影响PA激素的分泌和 体外侵袭。为了验证这些假说，我们的目标是：1)使用整合的表观基因组图谱和RNA 分析手术切除的侵袭性和非侵袭性PAS的测序方法 多机构联盟，2)利用DNA发现新的分子定义的PA亚型 甲基化和基因表达分析，随后发展了一种基于分子的 分类和统一的诊断方案，3)确定候选DNA甲基化和基因 与PA激素分泌和侵袭相关的表达标记物，4)使用已建立的大鼠和 手术切除的人PA原代细胞株检测激素分泌和侵袭表型 在对优先基因的表达进行调控之后。对分子途径的理解 与PA激素分泌和侵袭相关的将为从业者提供更精确的 诊断信息和帮助开发有针对性的药物疗法以抑制或逆转PA荷尔蒙 过度分泌和侵袭，从而提高患者的生活质量和生存。派生的知识 这项研究可以帮助难治性PA患者缓解与 慢性激素分泌过多、药物治疗、放射治疗和重复手术。

Project Summary: DNA Methylation and gene expression variations influence pituitary adenoma hormonal function and invasive growth Pituitary Adenomas (PAs) are among the most common intracranial tumors, and may cause hypopituitarism, neurological deficits, and lethal hormonal oversecretion disorders such as Cushing's disease and acromegaly. Although typically benign, PA invasion into surrounding dura, bone, and brain is evident in nearly half of symptomatic patients and is the major barrier to achieving long-term tumor control, hormonal remission, and normalized patient survival. Genetic mutations do not play a major role in the development or behavior of non-familial PAs, and a major knowledge gap exists in understanding the molecular underpinnings of PA hormonal function and invasive growth. Alternatively, epigenetic (e.g., DNA methylation) and gene expression alterations are known to influence PA phenotype, but these effects vary with gene location and context. Our team performed the first epigenome-wide pilot study to explore the association of DNA methylation and gene expression with PA behavior, and validated several genes implicated in PA hormonal function and invasion. Using a similar workflow, our overall goal is to define the role that DNA methylation and gene expression play in PA hormonal secretion and invasion in a larger study stratified according to PA hormonal subtype and invasion status. We hypothesize that: 1) variation in DNA methylation and expression is associated with subtype-specific PA hormonal function and invasion; 2) DNA methylation and expression data can be used to identify novel molecularly-defined PA classes and complement current PA diagnostic schemes; and 3) modulated expression of prioritized genes of interest will affect PA hormonal secretion and invasion in vitro. To test these hypotheses, we aim to: 1) use integrative epigenomic profiling and RNA sequencing approaches to analyze surgically-resected invasive and noninvasive PAs derived from a multi-institutional consortium, 2) discover novel molecularly-defined PA subtypes using DNA methylation and gene expression analysis, followed by development of a molecularly-based classification and unified diagnostic scheme, 3) identify candidate DNA methylation and gene expression markers associated with PA hormonal secretion and invasion, 4) use established rat and surgically-resected human PA primary cell lines to test hormonal secretion and invasion phenotypes following modulation of expression of prioritized genes. Understanding the molecular pathways associated with PA hormonal secretion and invasion will provide practitioners with more precise diagnostic information and help to develop targeted drug therapies to curb or reverse PA hormonal oversecretion and invasion, thereby improving patient quality of life and survival. Knowledge derived from this study could help refractory PA patients by helping to mitigate lifelong risks associated with chronic hormone oversecretion, medications, radiation treatment, and repeat surgery.