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Gene Mutation Linked to Poor Survival in Children with Medulloblastoma

Thursday, February 11, 2010

Results from a small, retrospective study suggest that a single genetic mutation may be linked to poor survival in children with medulloblastoma, the most common type of pediatric brain tumor. In the study, released online February 8 in the Journal of Clinical Oncology, no patient with medulloblastoma whose tumor had a mutation in the TP53 gene was alive after 5 years, even though the large majority of patients were considered to be at average risk for disease progression after treatment, reported Dr. Cynthia Hawkins and colleagues from the Hospital for Sick Children in Toronto.

With modern treatment protocols, approximately 80 percent of average-risk patients with medulloblastoma—classified as such based on whether their tumor could be completely removed, their age, and whether they had metastases—survive for 5 years or more. “So we’ve identified a group of patients based on clinical factors who do well, on average, but still 20 percent of those patients are dying and we don’t know why,” Dr. Hawkins said.

The study involved 108 children treated for medulloblastoma between 1995 and 2007. Tumor samples were available for DNA sequencing from 49 of these children, and 8 had a TP53 mutation. TP53 mutations were strongly associated with early tumor recurrences. Of the 27 patients considered to be at average risk from this group of 49 children, 8 died within 5 years, 6 of whom had TP53 mutations.

Overall, 5-year survival rates for patients with TP53 mutations was 0 percent, compared with 74 percent for patients whose tumors had a normal, or wild-type, TP53 gene. Among the average-risk patients, the discrepancy for progression-free survival was greater still, 0 percent compared with 87 percent.

“All patients with TP53-mutated medulloblastomas presented with local disease and experienced recurrence locally,” the researchers wrote. “This implies that, as opposed to other molecular alterations found in medulloblastoma that are associated with dissemination, TP53 mutation causes an aggressive phenotype through other mechanisms.”

The finding of an association between TP53 status and medulloblastoma outcome is “important information,” said Dr. Javed Khan of NCI’s Pediatric Oncology Branch in the Center for Cancer Research. Dr. Khan concurred with the authors that the findings need to be validated in a larger, prospective study.

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