COG studies of gene amplification in rhabdomyosarcoma

横纹肌肉瘤基因扩增的 COG 研究

• 批准号: 6969858
• 负责人: FREDERIC G BARR
• 金额: $ 43.35万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6969858
• 关键词: biomarker; clinical research; comparative genomic hybridization; cyclin dependent kinase; fluorescent in situ hybridization; gene expression; human tissue; molecular oncology; natural gene amplification; neoplasm /cancer genetics; oncoproteins; pathologic process; protein structure function; rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a family of myogenic soft tissue cancers with two main subtypes, embryonal (ERMS) and alveolar (ARMS), which were first identified by histologic criteria and then associated with distinct clinical characteristics and genetic events. Within these subtypes, there is clinical and genetic heterogeneity, consistent with the premise that subtype-specific "primary" genetic events collaborate with various "secondary" events during RMS pathogenesis and give rise to subsets with varying clinical features. This application will focus on amplification as one category of collaborating oncogenic events and molecular markers. Comparative genomic hybridization (CGH) studies revealed that amplification occurs frequently in ARMS and localized the most common amplicons to the 12q13-15 and 2p24 chromosomal regions. Pilot studies of ARMS cases from the IRS-IV clinical trial identified 12q13-15 amplification in 26% of cases and revealed two distinct amplicons, one including CDK4 and another including MDM2. Comparison with gene expression indicated that CDK4 but not MDM2 amplification results in overexpression. However, correlation with clinical data indicated a significant association of MDM2 but not CDK4 amplification with poor outcome leading to the hypothesis that there is an amplified target gene near MDM2 that has a significant impact on the clinical behavior of ARMS. In CGH studies of the ERMS subtype, a 10-fold higher frequency of amplification was found in ERMS cases with anaplasia. Furthermore, recent clinical studies revealed a significantly poorer survival in ERMS cases with anaplasia and therefore amplification is postulated to contribute to the aggressive phenotype of ERMS cases with anaplasia. In this research project, members of the Soft Tissue Sarcoma Committee of the Children's Oncology Group will utilize tumor material collected by its tumor bank to explore the clinical significance of gene amplification in RMS. Array-based CGH and expression analyses will be used to define the major genomic targets of the 12q13-15 and 2p24 amplicons in ARMS, screen for other amplicons, and analyze the clinical significance of these events in a large cohort of ARMS cases. Furthermore array-based CGH will be used to identify the major amplicons associated with anaplasia in ERMS, and determine the association of anaplasia and amplification with clinical outcome in ERMS. In summary, these studies will provide a detailed investigation of amplification in both ARMS and ERMS, and incorporate amplification into the evolving set of molecular markers useful for risk-based stratification of RMS patients.

横纹肌肉瘤（RMS）是一个具有两个主要亚型的肌源性软组织癌家族，胚胎（ERMS）和肺泡（ARM）首先通过组织学标准鉴定，然后与不同的临床特征和遗传事件相关。在这些亚型中，存在临床和遗传异质性，这与RMS发病机理中各种“次级”事件合作的前提与以下前提相一致，并引起具有不同临床特征的子集。该应用将集中在扩增作为协作的致癌事件和分子标记的一种类别。比较基因组杂交（CGH）研究表明，扩增经常发生在臂中，并将最常见的扩增子局部到12q13-15和2p24染色体区域。 IRS-IV临床试验中的武器病例的试点研究确定了26％的12q13-15扩增 揭示了两个不同的扩增子，一个包括CDK4，包括MDM2。与基因表达的比较表明，CDK4而不是MDM2扩增会导致过表达。然而，与临床数据的相关性表明MDM2的显着关联，但CDK4扩增与结果不佳，导致假设MDM2附近有一个扩增的靶基因对臂的临床行为产生重大影响。在对ERMS亚型的CGH研究中，在异性疾病的ERMS病例中发现了扩增的频率高10倍。此外，最近的临床研究表明，在ERMS患有异常病例中的生存率明显较差，因此假设扩增有助于侵略性 ERMS病例的表型。在该研究项目中，儿童肿瘤学组软组织肉瘤委员会的成员将利用其肿瘤库收集的肿瘤材料来探索RMS基因扩增的临床意义。基于阵列的CGH和表达分析将用于定义手臂中12q13-15和2p24扩增子的主要基因组靶标，筛选其他扩增子，并在大量的武器病例中分析这些事件的临床意义。此外，基于阵列的CGH将用于识别与ERMS中与变形的主要扩增子，并确定Anaplasia和ERMS中临床结果与临床结果的关联。总而言之，这些研究将对武器和ERMS的扩增进行详细的研究，并纳入 放大对RMS患者的基于风险的分层有用的不断发展的分子标记。