Original articlesClinical Correlations of Genetic Changes by Comparative Genomic Hybridization in Ewing Sarcoma and Related Tumors
Introduction
Ewing sarcoma is a highly malignant primitive tumor characterized by uniform, densely packed small cells with round nuclei [1]. Tumors very closely related to Ewing sarcoma are atypical Ewing sarcoma, primitive neuroectodermal tumor (PNET), and esthesioneuroblastoma. These tumors can arise in bone or soft tissue. With current treatment regimens, 5-year disease-free survival rates are more than 50% 2, 3. The most important clinical prognostic parameters are tumor size [4], location [5], and histologic response to chemotherapy [6]. Patients with metastatic disease at presentation have a poor prognosis 3, 5.
The characteristic translocation t(11;22)(q24;q12) is seen in more than 80% of Ewing sarcoma and related tumors by cytogenetics [7]. The translocation fuses EWS (22q12) with FLI1 (11q24), a member of the ETS family of transcription factors 8, 9. The translocation results in the expression of a chimeric protein that acts as a more potent transcription activation factor than normal FLI1 [10]. In some tumors, EWS fuses with other ETS members: ERG (21q22) [11], ETV1 (7p22) [12], E1AF (17q21) [13], and FEV (2q33) [14]. Fusion of different ETS genes to EWS leads to a similar tumor phenotype, and no correlations between different translocation partners and clinical features or prognosis have been detected. Several EWS-FLI1 and EWS-ERG transcript types, with different breakpoints resulting in different exon-exon combinations, have been reported [11]. In two recent studies, fusion type I [9] was associated with a better prognosis 15, 16.
Secondary changes common in Ewing sarcoma and related tumors are trisomy 8, trisomy 12, and der(1;16), the last with different breakpoints reported but leading often to trisomy of 1q and monosomy of 16q. Trisomy 8 has been reported in 44–56% of the cases 17, 18, 19 and trisomy 12 in 29% [18] and 33% [17]. Der(1;16) has been detected in 17–18% 18, 19. These changes were also detected in our first comparative genomic hybridization (CGH) study of Ewing sarcoma and related tumors; copy number increases of chromosome 8, chromosome 12, and of 1q21∼q22 were detected with frequencies of 35%, 25%, and 25% [20]. Whether these secondary aberrations have prognostic significance is not known. In our previous study, statistical analysis was carried out with 11 patients [20]. The estimated 5-year survival rates were 78% and 50% in cases without and with a gain at 1q21∼22 (P = 0.57), 84% and 50% without and with a gain of chromosome 8 (P = 0.16), and 78% and 50% without and with a gain of chromosome 12 (P = 0.3) [20]. In the present study, we increased the number of patients and evaluated whether secondary aberrations detected by CGH have prognostic value in Ewing sarcoma and related tumors.
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Patients and Tumor Specimens
Twenty-eight samples of Ewing sarcoma and related tumors from 28 patients were obtained for the analysis (Table 1). Sixteen samples were obtained from the Helsinki University Central Hospital, five from the Rizzoli Institute, two from the Turku University Central Hospital, and five from the Scandinavian Sarcoma Group. The samples were obtained from primary tumors before the initiation of therapy.
The cases were classified as Ewing sarcoma and related tumors on the basis of a combined cytologic,
Outcome of the Patients
Seventeen (61%) of the patients are alive with no evidence of the disease after a median follow-up of 60 months (range, 10–86 months). Eleven patients (39%) died of the disease after a median follow-up of 19 months (range, 2–33 months). Eight patients had distant metastases at the time of the diagnosis: six of these patients died of the disease after a median of 11 months of follow-up, and two patients are alive with no evidence of disease.
Comparative Genomic Hybridization
Twenty-one of 28 tumors (75%) had changes in CGH.
Discussion
The findings of the present study show that DNA sequence copynumber aberrations are infrequent in Ewing sarcoma and related tumors, as only a mean of 1.9 aberrations per tumor was detected. High-level amplifications were rare. These findings indicate the importance of the characteristic translocation t(11;22)(q24;q12) in the tumorigenesis of these tumors. The findings are similar to those in biphasic synovial sarcomas [29]. With the low number of changes, these tumors differ from other
Acknowledgements
The study was supported by the Clinical Research Institute of Helsinki University Central Hospital, Helsinki University Central Hospital, and Leiras Research Foundation. We thank Dr. Kindblom (Sahlgren University Hospital, Gothenburg), Dr. Halvorsen (University Hospital, Trondheim), and Dr. Sundström (Academic Hospital, Uppsala) for providing samples.
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