Congenital melanocytic naevus syndrome is caused by a post-zygotic mutation in codon 61 of NRAS, predisposing to melanoma development in affected tissues
التفاصيل البيبلوغرافية
العنوان:
Congenital melanocytic naevus syndrome is caused by a post-zygotic mutation in codon 61 of NRAS, predisposing to melanoma development in affected tissues
Congenital melanocytic naevus (CMN) syndrome is the association of large or multiple CMN with neurological abnormalities, characteristic facial features, and an increased risk of melanoma that is not restricted to the skin. The genetic basis of the syndrome has previously been unknown, although various somatic mutations have been described in individual skin lesions. We hypothesised that one of these mutations might occur early in embryogenesis, leading to somatic mosaicism. 55 cutaneous, neurological, and blood samples were obtained from 15 accurately phenotyped patients with multiple CMN, and blood samples were taken from a further 44 patients with CMN. Site-directed mutagenesis generated restriction enzyme sites unique to the normal DNA sequence of codon 61 of NRAS (MIM 164790), allowing selective amplification of mutant alleles in mosaic tissue. Oncogenic missense mutations in codon 61 of NRAS were found in the affected neurological and cutaneous tissues of 12 of 15 patients, in a somatic mosaic pattern. In ten patients the heterozygous mutation was c.181C>A, p.Q61K, and in two c.182A>G, p.Q61R. No mutations were found in unaffected tissues or blood. Investigation of the primary melanoma samples in two patients revealed loss of heterozygosity at NRAS in one patient, and deletion of a region of chromosome 9p including CDKN2A (MIM 600160), a known melanoma gene, in both patients. CMN syndrome is therefore a mosaic RASopathy. This mosaicism underpins the associated risk of malignant melanoma and non-melanocytic central nervous system tumours by acting as a first hit in a multi-hit model of tumorigenesis. Funding Wellcome Trust.
