Molecular Profiling and Candidate Gene Analysis in Pediatric Gliomas

描述(申请人提供)：儿童低级别胶质瘤是儿童最常见的实体肿瘤。尽管应用了多种细胞遗传学和分子生物学方法，但与儿童低度恶性胶质瘤发生发展相关的主要遗传学事件在很大程度上是未知的。尽管大多数儿童可能只需手术就能治愈， 肿瘤可能会复发。通常复发的恶性程度较高，并可能对治疗产生抗药性。目前还没有组织学或生物标志物可以用来确定哪些患者的复发风险更高。随着阵列技术的最新发展，我们现在有机会以极高的分辨率表征儿童胶质瘤的基因组变化。我们假设使用这些方法可以检测到特定的非随机染色体不平衡。在本申请中，我们提出了三个具体目标。在目标1中，我们将使用ILumina的550K单多态性核苷酸阵列分析一系列儿童星形细胞瘤和神经节胶质瘤。染色体的获得和丢失，以及拷贝数中性杂合性丢失的区域将被识别。在目标2中，我们将使用荧光原位杂交、DNA和RNA分析以及免疫组织化学相结合的方法来验证阵列结果并确定候选基因。在目标3中，将分析一系列来自儿童和成人的低级别和高级别胶质瘤的特定标记物和潜在候选基因，以确定 针对不同患者群体的标记或基因组改变。这项研究的最终目标是确定特定的标记物，这些标记物可以作为儿童胶质瘤的诊断、预后和最终治疗的辅助手段。 公共卫生相关性：儿童胶质瘤是儿童最常见的实体肿瘤类型。我们将使用高密度单核苷酸多态性阵列来检测新的染色体 这些肿瘤的变化。我们的研究将为最终确定导致胶质瘤发展或进展的基因奠定基础，从而允许开发基于生物学的治疗策略。

DESCRIPTION (provided by applicant): Pediatric low-grade gliomas constitute the most common group of solid tumors in children. Despite the utilization of a variety of cytogenetic and molecular approaches, the primary genetic events associated with the development of pediatric low-grade gliomas are largely unknown. Although the majority of children may be cured with surgery alone, tumors can recur. Often the recurrences are of a higher malignancy grade, and may be resistant to treatment. There are currently no histologic or biologic markers that can be used to identify which patients are at an increased risk for recurrence. With recent developments in array technology, we now have the opportunity to characterize the genomic alterations in pediatric gliomas at an extremely high level of resolution. We hypothesize that specific non-random chromosomal imbalances will be detected using these approaches. In this application, we propose three specific aims. In aim 1, we will analyze a series of pediatric astrocytomas and gangliogliomas using 550K single polymorphism nucleotide arrays from Ilumina. Chromosomal gains and losses, as well as regions of copy number neutral loss of heterozygosity will be identified. In aim 2, we will validate the array results and identify candidate genes using a combination of fluorescence in situ hybridization, DNA and RNA analysis and immunohistochemistry. In aim 3, specific markers and potential candidate genes will be analyzed in a series of low and high-grade gliomas from both children and adults to determine the specificity of the markers or genomic alterations for different groups of patients. The ultimate goal of this Research is to identify specific markers that can be used as an aid in the diagnosis, prognosis, and ultimate treatment of gliomas in children. PUBLIC HEALTH RELEVANCE: Pediatric gliomas are the most common types of solid tumors in children. We will use high-density single nucleotide polymorphism arrays to detect novel chromosomal changes in these tumors. Our studies will form the basis for ultimate identification of the genes that are responsible for the development or progression of gliomas, thus allowing for development of biologically based treatment strategies.