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Novel mutations in melanoma

Melanoma constitutes one of the most frequent cancers with a high morbidity rate. Nearly 60 % of cases present with mutations in the BRAF kinase (at position 600), but additional genetic events are thought to be required for malignant transformation.

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Metastatic malignant melanoma has poor prognosis and although inhibitors targeting mutated BRAF have demonstrated clinical efficacy, acquired resistance hampers the curative potential of these strategies. However, the discovery of transforming mutations is complicated by the abundance of passenger mutations caused by ultraviolet light exposure. Seeking to address this issue, scientists on the EU-funded 'Gene discovery in melanoma progression and therapeutic resistance' (MELANOMA GENES) project used an animal model of the disease. This transgenic mouse harboured the human BRAF protein mutation specifically in mouse melanocytes and presented skin hyperpigmentation and melanoma formation. The long latency of cancer onset in this mouse presented an ideal scenario for screening for driver mutations. Researchers bred this mouse with the mouse that carries the Sleeping Beauty transposon, a DNA element capable of jumping between positions in the genome. They observed a significant acceleration of tumourigenesis and analysed the transposon insertion sites to identify the genes responsible for this observation. A list of genes with established roles in the formation of melanoma were identified. The Enhancer of Polycomb 1 (EPC1) gene was one of the most commonly altered genes, and given its involvement in other cancers scientists decided to further explore its role as a tumour suppressor in melanoma. Suppression of EPC1 expression significantly affected melanoma cell proliferation and transformation. Furthermore, the consortium was interested in unveiling the genes responsible for drug resistance. In this context, they treated melanoma mice with a BRAF inhibitor and waited for the emergence of drug-resistant tumours. Genomic sequencing identified eight genetic loci that were mutated following drug treatment. Functional evaluation of these genes indicated the involvement of the PI3K pathway in the emergence of drug resistance. Apart from providing fundamental insight into the genetic aetiology of melanoma, the findings of the MELANOMA GENES study have clinical implications. They are expected to drive research and development into a new era of melanoma drugs with improved clinical efficacy and minimal drug resistance.

Keywords

Melanoma, BRAF kinase, drug resistance, EPC1, PI3K

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