Neurofibromatosis type 1-associated tumours: Their somatic mutational spectrum and pathogenesis

Neurofibromatosis type 1 (NF1) is a common auto-somal dominantly inherited tumour predisposition syndrome affecting 1/3,000-4,000 individuals worldwide [1,2]. NF1 manifests a variety of characteristic features that include: hyperpigmentary abnormalities of the skin (café-au-lait macules and inguinal/axillary freckling), iris hamartomas (Lisch nodules) and the growth of benign peripheral nerve sheath tumours (neurofibromas) in the skin. Neurofibromas display many different subtypes and are associated with a variety of different clinical complications. Cutaneous neurofibromas are present in almost all adult NF1 patients [3]. Plexiform neurofibromas (PNFs), a more diffuse type of tumour, are present in 30-50 per cent of NF1 patients, and some 10-15 per cent of these benign tumours are transformed to malignant peripheral nerve sheath tumours (MPNSTs), the main cause of morbidity in NF1 [4]. Other NF1-associated clinical features include: skeletal abnormalities, such as tibial bowing or pseudoarthrosis; skeletal and orbital dysplasia; ostopenia/osteoporosis; aqueduct stenosis; macrocephaly; pectus excavatum; short stature; cardiovascular malformations; learning difficulties; and attention deficit disorder [1,5].Cancer represents the transformation of a cell whose growth is normally tightly controlled into one that is no longer under strict regulation, allowing the cell to multiply uncontrollably and even metastasize. This dramatic alteration in cellular control arises as a consequence of the accumulation of genetic and epigenetic changes: activated oncogenes speed up cell growth through the acquisition of gain-of-function mutations, whereas tumour suppressor genes (TSGs) promote progression by acquiring loss-of-function mutations. TSGs typically encode proteins involved in growth regulation, apoptosis initiation, cellular adhesion and DNA repair. In accordance with Knudson's two-hit hypothesis,[6] both alleles of a TSG must be inactivated for cellular transformation to o