Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Lindblad-Toh, K. et al. Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays. Nature Biotechnol. 18, 1001–1005 (2000)

    CAS  Article  Google Scholar 

  2. 2

    Lieberfarb, M. E. et al. Genome-wide loss of heterozygosity analysis from laser capture microdissected prostate cancer using single nucleotide polymorphic allele (SNP) arrays and a novel bioinformatics platform dChipSNP. Cancer Res. 63, 4781–4785 (2003)

    CAS  PubMed  Google Scholar 

  3. 3

    Mei, R. et al. Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays. Genome Res. 10, 1126–1137 (2000)

    CAS  Article  Google Scholar 

  4. 4

    Zhao, X. et al. An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. Cancer Res. 64, 3060–3071 (2004)

    CAS  Article  Google Scholar 

  5. 5

    Bignell, G. R. et al. High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res. 14, 287–295 (2004)

    CAS  Article  Google Scholar 

  6. 6

    Stinson, S. F. et al. Morphological and immunocytochemical characteristics of human tumour cell lines for use in a disease-oriented anticancer drug screen. Anticancer Res. 12, 1035–1053 (1992)

    CAS  PubMed  Google Scholar 

  7. 7

    Ross, D. T. et al. Systematic variation in gene expression patterns in human cancer cell lines. Nature Genet. 24, 227–235 (2000)

    CAS  Article  Google Scholar 

  8. 8

    Roschke, A. V. et al. Karyotypic complexity of the NCI-60 drug-screening panel. Cancer Res. 63, 8634–8647 (2003)

    CAS  PubMed  Google Scholar 

  9. 9

    Nishizuka, S. et al. Proteomic profiling of the NCI-60 cancer cell lines using new high-density reverse-phase lysate microarrays. Proc. Natl Acad. Sci. USA 100, 14229–14234 (2003)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Monks, A., Scudiero, D. A., Johnson, G. S., Paull, K. D. & Sausville, E. A. The NCI anti-cancer drug screen: a smart screen to identify effectors of novel targets. Anticancer Drug Des. 12, 533–541 (1997)

    CAS  PubMed  Google Scholar 

  11. 11

    Eisen, M. B., Spellman, P. T., Brown, P. O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Golub, T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999)

    CAS  Article  Google Scholar 

  13. 13

    Steingrimsson, E., Copeland, N. G. & Jenkins, N. A. Melanocytes and the Microphthalmia Transcription Factor Network. Annu. Rev. Genet. 38, 365–411 (2004)

    CAS  Article  Google Scholar 

  14. 14

    Camp, R. L., Dolled-Filhart, M., King, B. L. & Rimm, D. L. Quantitative analysis of breast cancer tissue microarrays shows that both high and normal levels of HER2 expression are associated with poor outcome. Cancer Res. 63, 1445–1448 (2003)

    CAS  PubMed  Google Scholar 

  15. 15

    Hemesath, T. J., Price, E. R., Takemoto, C., Badalian, T. & Fisher, D. E. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature 391, 298–301 (1998)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Price, E. R. et al. Lineage-specific signalling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia. J. Biol. Chem. 273, 17983–17986 (1998)

    CAS  Article  Google Scholar 

  17. 17

    Wu, M. et al. c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi. Genes Dev. 14, 301–312 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Loercher, A. E., Tank, E. M., Delston, R. B. & Harbour, J. W. MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A. J. Cell Biol. 168, 35–40 (2005)

    CAS  Article  Google Scholar 

  19. 19

    Carreira, S. et al. Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression. Nature 433, 764–769 (2005)

    ADS  CAS  Article  Google Scholar 

  20. 20

    Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002)

    ADS  CAS  Article  Google Scholar 

  21. 21

    Jafari, M. et al. Analysis of ras mutations in human melanocytic lesions: activation of the ras gene seems to be associated with the nodular type of human malignant melanoma. J. Cancer Res. Clin. Oncol. 121, 23–30 (1995)

    CAS  Article  Google Scholar 

  22. 22

    Kubo, A. et al. The p16 status of tumour cell lines identifies small molecule inhibitors specific for cyclin-dependent kinase 4. Clin. Cancer Res. 5, 4279–4286 (1999)

    CAS  PubMed  Google Scholar 

  23. 23

    McGill, G. G. et al. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 109, 707–718 (2002)

    CAS  Article  Google Scholar 

  24. 24

    Du, J. et al. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell 6, 565–576 (2004)

    CAS  Article  Google Scholar 

  25. 25

    Chu, W. et al. Tyrosinase-related protein 2 as a mediator of melanoma specific resistance to cis-diamminedichloroplatinum(II): therapeutic implications. Oncogene 19, 395–402 (2000)

    CAS  Article  Google Scholar 

  26. 26

    Berger, R. et al. Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells. Cancer Res. 64, 8867–8875 (2004)

    CAS  Article  Google Scholar 

  27. 27

    Chen, C. D. et al. Molecular determinants of resistance to antiandrogen therapy. Nature Med. 10, 33–39 (2004)

    Article  Google Scholar 

  28. 28

    Berger, A. J. et al. Automated quantitative analysis (AQUA) of HDM2 expression in malignant melanoma shows association with early stage disease and improved outcome. Cancer Res. (in the press)

  29. 29

    Rubin, M. A. et al. Overexpression, amplification, and androgen regulation of TPD52 in prostate cancer. Cancer Res. 64, 3814–3822 (2004)

    CAS  Article  Google Scholar 

Download references


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.).

Author information



Corresponding author

Correspondence to William R. Sellers.

Ethics declarations

Competing interests

The GEO accession number is GSE2520. Reprints and permissions information is available at 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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing