Abstract
10028 Background: Ewing Family Tumors (EFTs) metastasize by hematogeneous spread. Because of its dismal cure rate, targeting subclinical disease is particularly relevant. Genome-wide gene expression array analysis can uncover novel genes differentially expressed in tumors over normal marrow/blood, which may have clinical potentials as markers of minimal residual disease (MRD). Methods: Gene expression array data were obtained on 28 EFT tumors and 10 EFT cell lines using the Affymetrix U133 gene chip. Ten genes with high tumor to blood ratios were identified. Quantitative RT-PCR was performed to study (1) the dynamic range of detection of rare tumor cells (frequency of 10-7 to 10-4), (2) the gene expression in normal blood and marrow samples, (3) the gene expression among EFT tumors, and (4) the prognostic impact of marker positivity in EFT patients with histologically negative marrows. Results: Of the 10 genes, 5 genes, namely six transmembrane epithelial antigen of the prostate 1 [STEAP1], cyclin D1 [CCND1], plakophilin 1 [PKP1], transmembrane protein 47 [TMEM47], and NKX2.2 transcription factor [NKX2.2] were chosen for further analyses. This was based on their steep linear dynamic range in tumor cells seeded in normal mononuclear cells and consistently high expression among EFT tumor samples. Among 53 EFT patients with histologically negative marrow samples, a marker was classified as positive if the gene transcript level was above the upper limit of normal, defined as mean + 2SD of 26 normal blood and marrow samples. Of the 5 markers tested, STEAP1 positivity in marrow samples was highly correlated with survival with new metastasis in Kaplan Meier analysis (p=0.001). Conclusions: This gene expression array-based approach identified STEAP1 as a promising surrogate MRD marker of metastatic EFT with potential prognostic importance. Its clinical utility will need to be further tested in large patient cohorts. No significant financial relationships to disclose.
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