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）是肌源性软组织癌的一个家族，具有两个主要亚型，胚胎型（ERMS）和腺泡型（ARMS），其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，这与亚型特异性“原发性”遗传事件在RMS发病过程中与各种“继发性”事件协作并产生具有不同临床特征的子集的前提一致。本申请将集中在扩增作为一类合作致癌事件和分子标记。比较基因组杂交（CGH）研究表明，扩增频繁发生在ARMS和本地化的最常见的扩增子12 q13 -15和2 p24染色体区域。IRS-IV临床试验中ARMS病例的初步研究发现，26%的病例存在12 q13 -15扩增， 显示了两种不同的扩增子，一种包括CDK 4，另一种包括MDM 2。与基因表达的比较表明，CDK 4而不是MDM 2的扩增导致过表达。然而，与临床数据的相关性表明MDM 2扩增而非CDK 4扩增与不良结局显著相关，从而导致假设MDM 2附近存在对ARMS临床行为具有显著影响的扩增靶基因。在ERMS亚型的CGH研究中，在伴有间变性的ERMS病例中发现了10倍的扩增频率。此外，最近的临床研究表明，在ERMS病例中，存在间变性的患者的生存率明显较差，因此扩增被假定为有助于侵袭性增殖。 ERMS病例的表型为间变性。在这项研究计划中，儿童肿瘤学小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，探讨基因扩增在RMS中的临床意义。基于阵列的CGH和表达分析将用于确定ARMS中12 q13 -15和2 p24扩增子的主要基因组靶标，筛选其他扩增子，并分析这些事件在大型ARMS病例队列中的临床意义。此外，基于阵列的CGH将用于鉴定与ERMS中间变性相关的主要扩增子，并确定间变性和扩增与ERMS中临床结局的相关性。总之，这些研究将提供ARMS和ERMS中扩增的详细调查，并结合 扩增成可用于RMS患者的基于风险的分层的分子标志物的进化集合。