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

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Figure 1: Increased MITF expression associated with chromosome 3p amplification in melanoma cell lines.
Figure 2: MITF maps to the epicentre of an amplicon present in a subset of malignant melanomas.
Figure 3: FISH, Kaplan–Meier and AQUA analysis of MITF in human melanoma samples.
Figure 4: A role for deregulated MITF in melanoma tumorigenesis and survival.

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Acknowledgements

We thank D. Scudiero and R. Camalier for provision of NCI60 cell lines and DNAs, O. Kabbarah and L. Chin for discussions and provision of reagents, F. Chen and C. Ladd-Acosta for excellent technical assistance, L. Ziaugra and S. Gabriel for assistance with the BRAF(V600E) genotyping assay, and M. Loda for expert advice. This work was supported by grants from the National Institutes of Health (L.A.G., M.A.R., D.L.R. and D.E.F.), the Swedish Wenner-Gren Foundation (H.R.W.), the Center of Molecular Medicine, Austrian Academy of Sciences (S.N.W.), the Howard Hughes Medical Institute (T.R.G.), the American Cancer Society (M.L.M.), the Flight Attendant Medical Research Institute (M.L.M.), the Doris Duke Foundation (D.E.F.), the Tisch Family Foundation (W.R.S.), and the Damon Runyon Cancer Research Foundation (W.R.S.).

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Correspondence to William R. Sellers.

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The GEO accession number is GSE2520. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure S1

Full cluster-ordered data set of NCI60 samples and SNPs (derived from CentXba™ array data). (PDF 63 kb)

Supplementary Figure S2

Melanoma tissue array clinical parameters-I: age, gender, and anatomic location of tumour. (PDF 85 kb)

Supplementary Figure S3

Melanoma tissue array clinical parameters -II: Clark level, Breslow depth, and immune response. (PDF 642 kb)

Supplementary Figure S4

Expression of dominant-negative MITF following adenoviral infection. (PDF 34 kb)

Supplementary Figure S5

Pharmacologic analysis of NCI60 cell lines with and without copy gain at the MITF (3p) locus. (PDF 68 kb)

Supplementary Figure Legends

Legends to accompany Supplementary Figures. (DOC 31 kb)

Supplementary Methods

This file contains additional SNP array descriptions, methods, and references. (DOC 83 kb)

Supplementary Table S1

Primer sequences used for quantitative and allele-specific PCR. (DOC 24 kb)

Supplementary Table S2

3p14 dosage, BRAF(V600E) mutation, and CDKN2A (p16) status in NCI60 melanoma cell lines. (DOC 26 kb)

Supplementary Table S3

MITF copy number distribution on the melanoma tissue microarray. (DOC 22 kb)

Supplementary Notes

MIAME Checklist (DOC 73 kb)

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Garraway, L., Widlund, H., Rubin, M. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005). https://doi.org/10.1038/nature03664

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