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

DNA 甲基化和基因表达变异影响垂体腺瘤的激素功能和侵袭性生长

• 批准号: 9767099
• 负责人: Gabriel Zada
• 金额: $ 53.07万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767099
• 关键词: Acromegaly; Address; Affect; Behavior; Benign; Brain; CRISPR/Cas technology; Candidate Disease Gene; Cell Culture Techniques; Cell Line; Cell Survival; Cessation of life; Chronic; Classification; Classification Scheme; Cluster Analysis; Complement; DNA; DNA Methylation; DNA Sequence Alteration; Data; Deterioration; Development; Diagnosis; Diagnostic; Disease; Disease remission; Dura Mater; Epigenetic Process; Exhibits; Formalin; Freezing; Gene Expression; Gene Expression Alteration; Gene Expression Profile; Gene Expression Profiling; Gene Mutation; Gene Silencing; Genes; Genome; Genomics; Goals; Growth; Hormonal; Hormone secretion; Hormones; Human; Hypopituitarism; In Vitro; Institutional Review Boards; Intracranial Neoplasms; Knowledge; Location; Methodology; Methods; Modality; Molecular; Neurologic; Neurologic Deficit; Operative Surgical Procedures; Outcome; Paraffin Embedding; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Pilot Projects; Pituitary Gland; Pituitary Gland Adenoma; Pituitary-dependent Cushing' s disease; Play; Precision therapeutics; Publishing Peer Reviews; Quality of life; Radiation therapy; Rattus; Refractory; Repeat Surgery; Research; Resected; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Scheme; Scientist; Somatic Mutation; Somatotropin; Subgroup; Surgeon; Testing; Time; Translating; Variant; base; bone; cell motility; clinically relevant; cohort; contextual factors; disability; disorder control; epigenome; epigenomics; experience; functional status; genome-wide; imaging study; improved; improved outcome; insight; interest; knock-down; methylome; molecular marker; multimodality; novel; overexpression; prognostic; small hairpin RNA; supervised learning; targeted treatment; transcriptome sequencing; tumor; tumor growth; vector

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.

DNA甲基化和基因表达变异影响垂体腺瘤 激素功能和侵入性生长 垂体腺瘤（PA）是最常见的颅内肿瘤之一， 垂体功能减退、神经缺陷和致死性激素分泌过多疾病，如库欣氏病 疾病和肢端肥大症。虽然PA通常是良性的，但它侵入周围的硬脑膜、骨和脑 在近一半有症状的患者中是明显的，并且是实现长期肿瘤的主要障碍。 控制、激素缓解和正常化的患者存活率。基因突变并不是 在非家族性PA的发展或行为中的作用，并且在以下方面存在重大知识差距： 了解PA激素功能和侵入性生长的分子基础。可选择地， 表观遗传（例如，DNA甲基化）和基因表达改变影响PA 表型，但这些影响随基因的位置和背景而变化。我们的团队首次 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，并验证了几个基因参与PA激素的功能和入侵。使用 类似的工作流程，我们的总体目标是确定DNA甲基化和基因表达在 在一项根据PA激素亚型分层的大型研究中，PA激素分泌和侵袭， 入侵状态我们假设：1）DNA甲基化和表达的变化与 亚型特异性PA激素功能和侵袭; 2）DNA甲基化和表达数据可以 用于鉴定新的分子定义的PA类别并补充当前的PA诊断方案; 和3）优先感兴趣基因的调节表达将影响PA激素分泌， 体外侵袭。为了验证这些假设，我们的目标是：1）使用整合的表观基因组分析和RNA 测序方法来分析从动脉瘤中切除的侵入性和非侵入性PA， 多机构联合体，2）使用DNA发现新的分子定义的PA亚型 甲基化和基因表达分析，然后开发基于分子的 分类和统一的诊断方案，3）鉴定候选DNA甲基化和基因 与PA激素分泌和侵袭相关的表达标志物，4）使用建立的大鼠和 切除的人PA原代细胞系用于测试激素分泌和侵袭表型 随后调节优先基因的表达。了解分子途径 与PA激素分泌和入侵相关的将为从业者提供更精确的 诊断信息，并帮助开发有针对性的药物治疗，以遏制或逆转PA激素 过度分泌和侵袭，从而提高患者的生活质量和生存率。获得的知识 这项研究可以帮助难治性PA患者，帮助减轻与 慢性激素分泌过多，药物治疗，放射治疗和重复手术。