Why do benign astrocytomas become malignant in NF1?

Many patients with NF1 develop severe medical complications over their life span, as they do the major NF1 manifestations—café-au-lait spots, skin-fold freckling, iris Lisch nodules, and neurofibromas.1,3,5⇓⇓ Forty to 60% of children will have learning disabilities, variable cognitive impairment,6,7⇓ attention difficulties, and impairment of gross and fine coordination.4,7⇓ Patients can also have abnormal brain development: megalencephaly, enlargement of the corpus callosum, increased overall white matter volume, and areas of abnormal signal on MRI (“unidentified bright objects” or UBO).8 Patients with NF1 may be shorter than the average person, have larger than average head circumferences, and may also have thoracic abnormalities.1,4⇓ Other disease manifestations include osseous and vascular dysplasias.1,3,5⇓⇓ Plexiform neurofibromas occur in 25 to 50% of patients with NF1, with an increase in incidence over the life of the patient, and may involve many regions of the body, causing neurologic or cosmetic deficits; they also may evolve to malignant peripheral nerve sheath tumors.1,3,9⇓⇓

Patients with NF1 have a risk of malignancy as high as four- to sixfold above normal, including primary CNS tumors, malignant peripheral sheath tumors, rhabdomyosarcomas, and various leukemias.1,9⇓ There is little evidence, however, for the existence of NF1 pedigrees with strong cancer predisposition.10 Of the CNS tumors, optic pathway gliomas are the most common, occuring in 10 to 20% of patients at risk.11,12⇓ Gliomas elsewhere in the brain and ependymomas …