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Clinical and Molecular Characteristics of Malignant Transformation of Low-Grade Glioma in Children

Alberto Broniscer, Suzanne J. Baker, Alina N. West, Melissa M. Fraser, Erika Proko, Mehmet Kocak, James Dalton, Gerard P. Zambetti, David W. Ellison, Larry E. Kun, Amar Gajjar, Richard J. Gilbertson, Christine E. Fuller

From the Departments of Oncology, Developmental Neurobiology, Biochemistry, Biostatistics, Radiological Sciences, and Pathology, St Jude Children's Research Hospital; Department of Interdisciplinary Sciences, University of Tennessee Health Sciences Center, Memphis, TN; and the Northern Institute for Cancer Research, University of Newcastle, Newcastle-upon-Tyne, United Kingdom

Address reprint requests to Alberto Broniscer, MD, Department of Oncology, St Jude Children's Research Hospital, Mail Stop 260, 332 North Lauderdale St, Memphis, TN 38105; e-mail: alberto.broniscer{at}stjude.org

PURPOSE: To analyze the clinical and molecular characteristics of malignant transformation (MT) of low-grade glioma (LGG) in children.

PATIENTS AND METHODS: The clinical, radiologic, and histologic characteristics of children treated at our institution who experienced MT of LGG were reviewed. Molecular alterations in these tumors were analyzed by fluorescent in situ hybridization, immunohistochemistry, and TP53 sequencing. Cumulative incidence estimate and risk factors for MT were determined for 65 patients with grade 2 astrocytoma treated at our institution during the study interval.

RESULTS: Eleven patients who experienced MT were identified (median age at diagnosis of LGG, 13.3 years). Initial diagnoses were grade 2 astrocytoma (n = 6) and other grade 1/2 gliomas (n = 5). The median latency of MT was 5.1 years. Histologic diagnoses after MT were glioblastoma (n = 7) and other high-grade gliomas (n = 4). The 15-year cumulative incidence estimate of MT among 65 patients with grade 2 astrocytoma was 6.7% ± 3.9%; no risk factor analyzed, including radiotherapy, was associated with MT. Tissue was available for molecular analysis in all patients, including nine with samples obtained before and after MT. TP53 overexpression was more common after MT. Deletions of RB1 and/or CDKN2A were observed in 71% of LGGs and in 90% of tumors after MT. PTEN pathway abnormalities occurred in 76% of patients. One of five oncogenes analyzed (PDGFRA) was amplified in one patient.

CONCLUSION: The molecular abnormalities that occur during MT of LGG in children are similar to those observed in primary and secondary glioblastoma in adults.

Supported in part by National Institutes of Health grants (Cancer Center Support [CORE] Grant No. P30 CA21765 and Grant No. P01 CA096832 to S.J.B); Musicians Against Childhood Cancer; the Noyes Foundation; the Ryan McGhee Foundation; and by the American Lebanese Syrian Associated Charities (ALSAC).

Presented in part at the 12th International Symposium on Pediatric Neuro-Oncology, Nara, Japan, July 6-9, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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