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

Nature. 2005 Jul 7;436(7047):117-22.. Published: 2005.07.06

Levi A. Garraway, Hans R. Widlund, Mark A. Rubin, Gad Getz, Aaron J. Berger, Sridhar Ramaswamy, Rameen Beroukhim, Danny A. Milner, Scott R. Granter, Jinyan Du, Charles Lee, Stephan N. Wagner, Cheng Li, Todd R. Golub, David L. Rimm, Matthew L. Meyerson, David E. Fisher and William R. Sellers

Abstract

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 cancer. 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.

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Supplemental Data

Description Link/Filename
Supplementary Figure S1 Garraway-s1.pdf
NCI 60 SNP array data http://dtp.nci.nih.gov/mtargets/mt_index.html
Supplementary Figure S2 Garraway-s2.pdf
Accession # GSE2520 http://www.ncbi.nlm.nih.gov/geo
Supplementary Figure S3 Garraway-s3.pdf
Supplementary Figure S4 Garraway-s4.pdf
Supplementary Figure S5 Garraway-s5.pdf
Supplementary Figure Legends Garraway-s6.doc
Supplementary Methods Garraway-s7.doc
Supplementary Table S1 Garraway-s8.doc
Supplementary Table S2 Garraway-s9.doc
Supplementary Table S3 Garraway-s10.doc
Supplementary Notes Garraway-s11.doc
Manuscript Garraway.pdf