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Detection of Mitochondrial DNA Mutations in the Tumor and Cerebrospinal Fluid of Medulloblastoma Patients¹

Institute for Molecular and Human Genetics, Georgetown University, Washington, DC, 20007 [L-J. C. W., M. L.]; Division of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030 [X-N. L., C. C. L.]; and Department of Pathology, Stanford University Medical Center, Stanford, California 94305 [H. V.]

Medulloblastoma is the most common malignant brain tumor in children. Although the prognosis has improved considerably, leptomeningeal spread of the tumor remains a significantly negative predictor of survival. Mitochondrial DNA (mtDNA) mutations have been detected in many types of human tumors but not in medulloblastomas. Using temporal temperature gradient gel electrophoresis, we have analyzed the entire mitochondrial genome in 15 cases of medulloblastoma and the corresponding cerebrospinal fluid (CSF) samples in 8 of 15 cases. Six of 15 cases (40%) showed at least one mtDNA mutation in each of the tumors. A total of 18 somatic mtDNA mutations was detected with one of the tumors having 11 mutations, of which 9 were novel. Seven of 8 CSF samples that were analyzed showed mtDNA mutations. One patient who showed persistent mtDNA mutation in the CSF collected at the end of therapy when there was no evidence of disease had a relapse 5 months later. In contrast, patients whose end-of-therapy CSF samples that showed either no detectable mtDNA mutation or different mutations from that of the tumor continue to be disease free. Our results demonstrate that mtDNA mutations are frequently found in medulloblastomas. The mtDNA alterations detected in CSF may be used as sensitive markers to monitor disease progression and predict relapse.

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