COG studies of gene amplification in rhabdomyosarcoma

横纹肌肉瘤基因扩增的 COG 研究

• 批准号: 7103702
• 负责人: FREDERIC G BARR
• 金额: $ 41.44万
• 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/7103702
• 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)是一种肌源性软组织癌家族，主要分为胚胎型(ERMS)和肺泡型(ARMS)两种亚型，这两种亚型最早由组织学标准确定，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，这与以下前提一致：在RMS发病过程中，亚型特有的“主要”遗传事件与各种“次要”事件协同作用，产生具有不同临床特征的亚群。这项应用将重点放在扩增作为一类合作的致癌事件和分子标记。比较基因组杂交(CGH)研究表明，扩增经常发生在手臂上，并将最常见的扩增片段定位在12q13-15和2p24染色体区域。来自IRS-IV临床试验的ARM病例的试点研究在26%的病例中发现12q13-15扩增 发现了两个不同的扩增片段，一个包括CDK4，另一个包括MDM2。与基因表达的比较表明，CDK4而不是MDM2扩增导致了过表达。然而，与临床数据的相关性表明，MDM2而不是CDK4扩增与不良结局显著相关，从而导致假设在MDM2附近存在扩增的靶基因，这对ARM的临床行为有显著影响。在ERMS亚型的CGH研究中，发现ERMS伴间变的病例扩增频率高出10倍。此外，最近的临床研究显示，有间变性的ERMS患者的存活率明显较低，因此推测扩增与侵袭性有关。 ERMS伴间变型病例的表型。在这项研究项目中，儿童肿瘤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基因扩增在RMS中的临床意义。基于阵列的CGH和表达分析将用于确定ARM中12q13-15和2p24扩增片段的主要基因组靶点，筛选其他扩增片段，并在大量ARM病例中分析这些事件的临床意义。此外，基于阵列的CGH将被用来识别ERMS中与间变相关的主要扩增片段，并确定ERMS中间变和扩增与临床结果的关系。总而言之，这些研究将提供对ARM和ERM放大情况的详细调查，并将 扩增到进化中的分子标记集，有助于RMS患者的基于风险的分层。