The Somatic Mutational Spectrum of the NF1 Gene

Abstract

Neurofibromatosis type 1 (NF1) affects 1/3,000–4,000 individuals worldwide and is caused by the inactivation of the NF1 tumour suppressor gene which encodes the protein neurofibromin. Consistent with Knudson’s two-hit hypothesis, NF1 patients harbouring a heterozygous germline NF1 mutation develop several NF1-associated tumours upon somatic inactivation of the second (wild-type) NF1 allele. Although the identification of somatic mutations in NF1 patients has always been problematic on account of the extensive cellular heterogeneity manifested by neurofibromas, their classification is a prerequisite for understanding the complex molecular mechanisms underlying NF1 tumorigenesis. Here, we have performed a meta-analysis of known somatic NF1 mutations identified in a range of NF1-associated neoplasms including peripheral nerve sheath tumours (neurofibromas), malignant peripheral nerve sheath tumours (MPNSTs), astrocytomas, gastrointestinal stromal tumours, gastric carcinoid, juvenile myelomonocytic leukaemia, glomus tumours, neuroblastomas, breast cancer and phaeochromocytomas. Comparison of the frequencies of the different types of somatic NF1 mutation so far observed with those of their previously reported germline counterparts reveals significant differences (p = 0.00014), with the somatic mutational spectrum being characterised by a greater proportion of nonsense mutations and a smaller proportion of splice-site mutations. Finally, C>T and G>A changes in CpG and CpHpG oligonucleotides resulting in missense/nonsense mutations in the NF1 gene were significantly overrepresented in the soma as compared to the germline (p = 0.007).