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Molecular analysis of astrocytomas presenting after age 10 in individuals with NF1

From the Departments of Neurology (Dr. Gutmann) and Neuropathology (Dr. Perry), Washington University School of Medicine, St. Louis, MO; Department of Laboratory Medicine and Pathology (Dr. James), Mayo Clinic Foundation, Rochester, MN; Department of Medical Genetics (Dr. Poyhonen), Family Federation of Finland, Helsinki, Finland; Department of Pathology and Neurosurgical Service (Dr. Louis), Massachusetts General Hospital and Harvard Medical School, Boston, MA; Department of Neurology (Dr. Ferner), Guy’s and St. Thomas’ Hospital Trust, London, UK; Department of Neurosurgery (Dr. Guha), University of Toronto, Canada; Department of Neurology (Dr. Hariharan), Seton Hall University, Edison, NJ; and Division of Medical Genetics, Department of Pediatrics (Dr. Viskochil), University of Utah, Salt Lake City, UT.

Address correspondence and reprint requests to Dr. David H. Gutmann, Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110; e-mail: gutmannd{at}neuro.wustl.edu

Background: Fifteen to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade astrocytomas. Although brain tumors are less common in teenagers and adults with NF1, recent studies have suggested that patients with NF1 are at a significantly increased risk of developing astrocytomas.

Objectives: To investigate the genetic basis for astrocytoma development in patients with NF1 beyond the first decade of life.

Methods: The authors performed molecular genetic analyses of 10 NF1-associated astrocytomas representing all World Health Organization (WHO) malignancy grades using fluorescence in situ hybridization, loss of heterozygosity, immunohistochemistry, and direct sequencing.

Results: Later-onset NF1-associated astrocytomas, unlike histologically identical sporadic astrocytomas, exhibit NF1 inactivation, supporting a direct association with NF1 rather than a chance occurrence. Furthermore, some of these astrocytomas have homozygous NF1 deletion. In addition, genetic changes observed in high-grade sporadic astrocytomas, including TP53 mutation and CDKN2A/p16 deletion, are also seen in NF1-associated high-grade astrocytomas.

Conclusions: Neurofibromatosis type 1–associated astrocytomas occurring in patients older than 10 years exhibit genetic changes observed in sporadic high-grade astrocytomas. Patients with neurofibromatosis type 1 and germline NF1 deletions may be at risk for developing late-onset astrocytomas.

Received March 19, 2003. Accepted in final form July 29, 2003.

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