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激素功能和侵袭性生长

基本信息

批准号：
10476992
负责人：
Gabriel Zada
金额：
$ 49.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10476992
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 DNA methylation profiling 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&apos 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 accurate diagnostics base bone cell motility clinically relevant cohort contextual factors disability disorder control epigenome epigenomics experience functional status gene expression variation genome-wide imaging study improved improved outcome insight interest knock-down methylome molecular marker multimodality novel overexpression personalized diagnostics precision drugs prognostic small hairpin RNA supervised learning targeted treatment transcriptome sequencing tumor tumor growth vector

项目摘要

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.

项目摘要：DNA甲基化和基因表达变化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，可能会导致垂体不足，神经系统缺陷和致命的激素过度分泌障碍，例如库欣疾病和肢端肥大。尽管通常是良性的，但PA侵入周围的硬脑膜，骨头和大脑在近一半的有症状患者中很明显，并且是实现长期肿瘤的主要障碍控制，荷尔蒙缓解和标准化患者的生存率。基因突变不发挥作用在非家庭PA的发展或行为中的作用，并且存在主要的知识差距了解PA激素功能和侵入性生长的分子基础。或者，已知表观遗传学（例如DNA甲基化）和基因表达改变会影响PA 表型，但这些影响随基因位置和背景而变化。我们的团队表演了第一个遍及表观基因组的初步研究，以探索DNA甲基化和基因表达与 PA行为，并验证了与PA激素功能和侵袭有关的几个基因。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 PA激素分泌和侵袭在一项大型研究中，根据PA激素亚型和入侵状态。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是用于鉴定新的分子定义的PA类并补充当前PA诊断方案； 3）调节优先级的感兴趣基因将影响PA激素分泌和体外入侵。为了检验这些假设，我们的目的是：1）使用整合表观基因组分析和RNA 测序方法是分析从A 多机构财团，2）使用DNA发现新型分子定义的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诊断方案，3）确定候选DNA甲基化和基因与PA激素分泌和入侵相关的表达标记，4）使用已建立的大鼠和通过手术定位的人PA主要细胞系测试激素分泌和浸润表型调节优先基因的表达。了解分子途径与PA荷尔蒙分泌和入侵相关的将为从业者提供更精确的诊断信息并有助于开发靶向药物疗法以遏制或反向PA激素分泌和入侵过度，从而改善了患者的生活质量和生存。知识得出从这项研究中可以通过减轻与之相关的终身风险来帮助难治性PA患者慢性激素分泌，药物，放射治疗和重复手术。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Clinical Implications of Pituitary Adenomas Exhibiting Dual Transcription Factor Staining: A Case Series of 27 Patients.

表现出双转录因子染色的垂体腺瘤的临床意义：27 名患者的病例系列。

DOI：
10.1016/j.wneu.2023.11.036
发表时间：
2024
期刊：
World neurosurgery
影响因子：
2
作者：
Bove,Ilaria;Cheok,StephanieK;Feng,JeffreyJ;Briggs,RobertG;Ruzevick,Jacob;Cote,DavidJ;Shah,Ishan;Little,Andrew;Laws,Edward;Castro,AnaValeria;Carmichael,John;Shiroishi,Mark;Hurth,Kyle;Zada,Gabriel
通讯作者：
Zada,Gabriel