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

Sebastian Spyk,David N Cooper,Nick Thomas,Meena Upadhyaya

doi:10.1186/1479-7364-5-6-623

Abstract

Somatic gene mutations constitute key events in the malignant transformation of human cells. Somatic mutation can either actively speed up the growth of tumour cells or relax the growth constraints normally imposed upon them, thereby conferring a selective (proliferative) advantage at the cellular level. 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 neurofibromas upon somatic mutation of the second, wild-type, NF1 allele. While the identification of somatic mutations in NF1 patients has always been problematic on account of the extensive cellular heterogeneity manifested by neurofibromas, the classification of NF1 somatic mutations is a prerequisite for understanding the complex molecular mechanisms underlying NF1 tumorigenesis. Here, the known somatic mutational spectrum for the NF1 gene in a range of NF1-associated neoplasms --including peripheral nerve sheath tumours (neurofibromas), malignant peripheral nerve sheath tumours, gastrointestinal stromal tumours, gastric carcinoid, juvenile myelomonocytic leukaemia, glomus tumours, astrocytomas and phaeochromocytomas -- have been collated and analysed.

Highlights

Neurofibromatosis type 1 (NF1) is a common autosomal 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, iris hamartomas (Lisch nodules) and the growth of benign peripheral nerve sheath tumours in the skin
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]
About 70 per cent of PNFs have been reported to display loss of heterozygosity (LOH) at the NF1 locus;[20] there is no obvious correlation between the type or location of germline NF1 mutations in NF1 patients and those of their somatic counterparts arising in their tumours.[20]

Summary

Introduction

Neurofibromatosis type 1 (NF1) is a common autosomal 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 (cafe-au-lait macules and inguinal/axillary freckling), iris hamartomas (Lisch nodules) and the growth of benign peripheral nerve sheath tumours (neurofibromas) in the skin. While the genetic basis of neurofibroma development is still not fully understood, biallelic NF1 inactivation does seem to be required, as all tumour cells harbour both a constitutional and a somatic NF1 gene mutation.[5] About 70 per cent of PNFs have been reported to display LOH at the NF1 locus;[20] there is no obvious correlation between the type or location of germline NF1 mutations in NF1 patients and those of their somatic counterparts arising in their tumours.[20]. There appears to be a marked difference between cutaneous neurofibromas, PNFs and MPNSTs, with 40 per cent, 79 per cent and 85 per cent, respectively, of somatic mutation events represented by LOH This may be explained in part by the extent of the molecular rearrangements in each tumour type; MPNSTs, for example, would be predicted to exhibit a greater extent of genetic aberration than a benign dermal neurofibroma. That treatment with multiple drugs may be more effective for NF1 tumours.[5]

Concluding remarks

30 UTR to 30 region

Findings

Mb deletion