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.
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