TRENDS in Molecular Medicine Vol.7 No.4 April 2001 http://tmm.trends.com 1471-4914/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4914(01)01955-4 157 Review David H. Gutmann* Nevada Reed Dept of Neurology, Pediatrics and Genetics, Washington University School of Medicine, Box 8111, 660 S. Euclid Avenue St Louis, MO 63110, USA. *e-mail: gutmannd@ neuro.wustl.edu Neurofibromatosis 1 and 2 (NF1 and NF2) are autosomal dominant disorders involving the nervous system, in which affected individuals have a propensity for developing both benign and malignant tumors. Because affected individuals have an increased risk of tumor formation, these disorders are classified as inherited cancer syndromes. NF1 affects 1 in 3500 individuals worldwide, whereas NF2 affects 1 in 30 000–42 000 individuals 1 . The prevalence of these syndromes is constant across all ethnic backgrounds and there is no gender predominance. NF1 and NF2 are clinically distinct disorders with different tumors developing in each disorder. Our ability to develop targeted clinical treatments for NF1 and NF2 is heavily dependent on an improved understanding of the molecular biological mechanisms underlying these disorders. Neurofibromatosis 1 Clinical features NF1 is also referred to as peripheral neurofibromatosis or Von Recklinghausen’s disease and is characterized by the development of pigmentary abnormalities, such as café-au-lait macules, skinfold freckling and iris hamartomas (Lisch nodules). In addition to these features, individuals with NF1 can develop skeletal and vascular abnormalities, and have a greater incidence of certain learning disabilities. Tumors that develop in individuals with NF1 include neurofibromas, optic pathway gliomas, and more rarely leukemias and pheochromocytomas. Although NF1 is inherited by an autosomal dominant mechanism, 50% of diagnosed cases appear to occur without a family history as a result of a new mutation. The diagnostic criteria for NF1 are listed in Box 1 (Ref. 2). The most common tumor associated with NF1, the neurofibroma, occurs in nearly all patients diagnosed with NF1. Neurofibromas are benign tumors that arise in association with peripheral nerves and are composed of a mixture of Schwann cells, fibroblasts and other cells. They are rarely present in childhood, but develop during puberty and pregnancy, suggesting a hormonal influence on tumor growth. Although they do not transform into malignant tumors, they can cause significant discomfort and disfigurement. Neurofibromas can occur anywhere on the skin and can also arise internally. One subtype of neurofibroma, the plexiform neurofibroma, is thought to represent a congenital lesion. In contrast to the more common discrete neurofibroma, these tumors can grow to enormous proportions and can cause significant morbidity by stimulating underlying bone growth or by compressing surrounding tissues. Additionally, plexiform neurofibromas harbor a 5% lifetime risk of transformation into malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are highly malignant and metastatic cancers with a high mortality and a poor response to chemotherapy and radiation. Other less common tumors seen in NF1 include optic pathway gliomas and myelodysplastic disorders (see below). NF1 gene Since the identification of the NF1 gene by positional cloning in 1990 (Refs 3–5), we have learned a great deal about the action of the NF1 gene product and how its dysfunction might result in tumor formation. The NF1 gene is located on chromosome 17q11.2, comprises 350 kb of genomic DNA, with 60 exons and encodes an mRNA of 11 to 13 kb 3–5 . The NF1 gene product, a protein called neuro-fibromin, is expressed in neurons, oligodendrocytes and Schwann cells 6 . It is also found ubiquitously in white blood cells, the adrenal medulla and many other cell types. In the brain, it is expressed in neuronal dendrites and axons, and might be associated with the neuronal cytoskeleton. Sequence analysis of neurofibromin reveals a region of homology with p120-GAP, the GTPase-activating protein (GAP) for the ras family of proto-oncogenes (Fig. 1a) 7 . Exons 20–27a of neurofibromin encode this ‘GAP related domain’ (GRD), which serves to accelerate the GTP-hydrolysis activity and thus downregulate p21-ras (ras). This is the only region of the neurofibromin protein whose biological function is known. The neurofibromatoses NF1 and NF2 are inherited cancer predisposition syndromes in which affected individuals are prone to development of mostly benign, but occasionally malignant, tumors. The NF1 and NF2 genes function as tumor suppressor genes (negative growth regulators), such that their loss of expression predisposes to tumor formation. Neurofibromin, the protein product of the NF1 gene, acts as a negative regulator of the ras proto-oncogene, to reduce cell growth. Merlin, the NF2 gene product, is involved in regulating cell proliferation and motility, and probably plays a role in integrating multiple cell-signaling pathways. By understanding the function of these tumor suppressors, we have a unique opportunity to develop targeted pharmacotherapeutic interventions for these disorders. Tumorigenesis in neurofibromatosis: new insights and potential therapies Nevada Reed and David H. Gutmann