The BRAFV600E Mutation Induces Blue Nevi, Epithelioid Melanocytoma and Malignant Peripheral Nerve Sheath Tumour-Like Malignant Melanoma in Mice
N Dhomen, FC Geyer, R Hayward, JS Reis-Filho, R Marais. Institute of Cancer Research, London, United Kingdom
Background: Several genetic alterations have been described in human melanomas, of which BRAF activating mutations are seen in 50-70% of the cases. The most prevalent mutation is V600E, which leads to the substitution of a glutamic acid for valine at position 600. BRAFV600E has been shown to drive proliferation in vitro and tumour maintenance and progression in vivo, suggesting it is a potent oncogene. Our aim was to investigate the role of BRAFV600E in melanomagenesis using an engineered mouse model where this mutation was specifically introduced in melanocytes.
Design: Using a Cre recombinase-based system, we have developed a mouse model of melanoma, driven by oncogenic Braf. Topical administration of tamoxifen results in a recombination event causing BrafV600E to be expressed specifically in melanocytes. Selected lesions were subjected to immunohistochemical analysis with antibodies against S100 protein and reverse transcriptase PCR (RT-PCR) for M-Mitf, Sox10, Pax3, c-kit, tyrosinase and Trp2.
Results: BrafV600E induced skin hyper-pigmentation and the progressive development of melanocytic lesions. 100% of the mice had multiple blue naevi throughout the body and 80% further developed large, dark and asymmetrical lesions in the eyelids and/or perianal areas, with morphological features consistent with the diagnosis of pigmented epithelioid melanocytoma. Finally, BrafV600E induced rapidly growing, infiltrating and destructive, oligomelanotic/amelanotic spindle cell tumours in 60-70% of the mice. Results of histopathological, immunohistochemical and RT-PCR analysis provided strong circumstantial evidence to suggest that these locally aggressive oligomelanotic/amelanotic spindle cell tumours were malignant peripheral nerve sheath tumour-like spindle cell malignant melanomas.
Conclusions: Our model demonstrates that activating BrafV600E mutations in melanocytes of mice lead to the development of lesions that recapitulate the histological and molecular features of benign and malignant human melanocytic neoplasms. Furthermore, this model may help understand the spectrum of blue cell lesions.
Tuesday, March 10, 2009 8:15 AM
Platform Session: Section E, Tuesday Morning