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

Project

SNP Analysis

Additional Projects/
Categories

Melanoma

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.

Authors

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

Publication Date

07/07/2005

Contact emails

Levi_Garraway@dfci.harvard.edu

Citation

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

Supplemental Information

URLs

Name	URL
NCI 60 SNP array data	http://dtp.nci.nih.gov/mtargets/mt_index.html
Accession # GSE2520	http://www.ncbi.nlm.nih.gov/geo

Files

Description	File
Supplementary Figure S1	Garraway-s1.pdf
Supplementary Figure S2	Garraway-s2.pdf
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