Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma

Abstract

Analysis of pharmacological and genetic data from the US National Cancer Institute's NCI60 collection of cancer cell lines has identified a novel DNA amplification event in human melanomas. It alters MITF gene expression to promote melanoma formation, probably in cooperation with mutated BRAF, another key melanoma gene. Amplification of MITF may also help melanoma cells resist destruction by drugs. This work identifies MITF itself as a possible drug target in melanoma, and may encourage future genomics efforts to identify genetic alterations in other cancers. Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer1,2,3,4,5. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of ‘lineage survival’ or ‘lineage addiction’ oncogenes required for both tissue-specific cancer development and tumour progression.