Approximately 30-50% of primary cutaneous melanomas have been found to arise from a pre-existing naevus yet the melanoma transformation rate of each naevus is extremely rare – despite the occurrence of oncogenic BRAF and NRAS mutations in 100% of all acquired naevi. The molecular hallmarks preventing these naevi from progressing to melanoma must be better characterised in order to develop melanoma prevention strategies.
Recently we performed whole exome sequencing of 30 naevi together with their matched perilesional and saliva-derived germline DNA. It was found that common reticular naevi (mostly with a junctional component) have a high number of copy number aberrations (CNA). Importantly, concurrent with the loss of tumour suppressor genes (e.g. CDKN2A, TP53, and NF1) was the loss of potent oncogenes (e.g. NRAS, MITF, and MDM2). We postulate that the balanced nature of these CNAs confers protection from transformation, thus keeping the lesion in the benign state.
Along with copy-number loss of these well-known genes, further interrogation of these data revealed a loss on chr8q24.3 which was frequently observed in 7/30 (23%) naevi. In the smallest region of overlap, the block of proliferation 1 (BOP1) gene was identified as a candidate for functional validation. BOP1 is part of the trimeric “PeBoW” complex, essential for ribosome biogenesis and cell cycle progression. In melanoma cell lines (MM96L, HT144, and MM253), we showed that knockdown of BOP1 using siRNA resulted in a significant reduction in cellular proliferation and 2D colony formation. Importantly however, this loss resulted in increased invasiveness and migration rate (live-cell scratch-wound) which suggests that BOP1 plays a role in melanoma progression by contributing to phenotype switching. Immunohistochemical assessment is underway in a naevus-melanoma progression series. In sum, we propose that loss of BOP1 in naevi is an early deleterious event involved in naevus progression to melanoma.