Skip to main content

Thank you for visiting nature.com. 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.

  • Letter
  • Published:

Molecular classification of cutaneous malignant melanoma by gene expression profiling

Abstract

The most common human cancers are malignant neoplasms of the skin1,2. Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease3,4. Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm2,3. Accordingly, though melanoma is thought to present with different ‘taxonomic’ forms, these are considered part of a continuous spectrum rather than discrete entities2. Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro, a feature of some highly aggressive metastatic melanomas5. Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Clustering of gene expression data.
Figure 2: Identifying genes which discriminate melanoma clusters.
Figure 3: Guiding gene cluster selection.
Figure 4: Variation in biological properties of melanoma clusters. a c, A representative member of the major melanoma cluster (UACC-1022).

Similar content being viewed by others

References

  1. Hall, H. I., Miller, D. R., Rogers, J. D. & Bewerse, B. Update on the incidence and mortality from melanoma in the United States. J. Am. Acad. Dermatol. 40, 35– 42 (1999).

    Article  CAS  Google Scholar 

  2. Weyers, W., Euler, M., Diaz-Cascajo, C., Schill, W. B. & Bonczkowitz, M. Classification of cutaneous malignant melanoma: a reassessment of histopathologic criteria for the distinction of different types. Cancer 86, 288– 299 (1999).

    Article  CAS  Google Scholar 

  3. Byers, H. R. & Bhawan, J. Pathologic parameters in the diagnosis and prognosis of primary cutaneous melanoma. Hematol. Oncol. Clin. North Am. 12, 717–735 ( 1998).

    Article  CAS  Google Scholar 

  4. McMasters, K. M., Sondak, V. K., Lotze, M. T. & Ross, M. I. Recent advances in melanoma staging and therapy. Ann. Surg. Oncol. 6, 467–475, ( 1999).

    Article  CAS  Google Scholar 

  5. Maniotis, A. J. et al. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol. 155, 739–752 ( 1999).

    Article  CAS  Google Scholar 

  6. DeRisi, J. et al. Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nature Genet. 14, 457– 460 (1996).

    Article  CAS  Google Scholar 

  7. Khan, J. et al. Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays. Cancer Res. 58, 5009– 5013 (1998)

    CAS  PubMed  Google Scholar 

  8. Perou, C. M. et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc. Natl Acad. Sci. USA 96, 9212–9217 (1999).

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Alizadeh, A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    Article  ADS  CAS  Google Scholar 

  11. Bittner, M., Meltzer P. & Trent J. Data analysis and integration: of steps and arrows. Nature Genet. 22, 213– 215 (1999).

    Article  CAS  Google Scholar 

  12. 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).

    Article  ADS  CAS  Google Scholar 

  13. Everitt, B. Applied Multivariate Data Analysis. (Oxford Univ. Press, New York, 1992)

    MATH  Google Scholar 

  14. Ben-Dor, A., Shamir, R. & Yakhini, Z. Clustering gene expression patterns. J. Comput. Biol. 6, 281–297 ( 1999).

    Article  CAS  Google Scholar 

  15. Adams, J. C. Characterization of cell-matrix adhesion requirements for the formation of fascin microspikes. Mol. Biol. Cell 8, 2345 –2363 (1997).

    Article  CAS  Google Scholar 

  16. Scott, G. & Liang, H. pp125FAK in human melanocytes and melanoma: expression and phosphorylation. Exp. Cell Res. 219, 197–203 (1995).

    Article  CAS  Google Scholar 

  17. Jannji, B., Melchior, C., Guon, V., Vallar, L. & Kieffer, N. Autocrine TGF-beta-regulated expression of adhesion receptors and integrin-llinked kinase in HT-144 melanoma cells correlates with their metastatic phenotype. Int. J. Cancer 83, 255–262 (1999).

    Article  Google Scholar 

  18. Hieken, T. et al. Beta1 integrin expression in malignant melanoma predicts occult lymph note metastases. Surgery 118, 669– 673 (1995).

    Article  CAS  Google Scholar 

  19. Van Belle, P. et al. Progression-related expression of beta3 integrin in melanomas and nevi. Hum. Pathol. 30, 562– 567 (1999)

    Article  CAS  Google Scholar 

  20. Woods, A., Longley, R., Tumova, S. & Couchman, J. Syndecan-4 binding to the high affinity heparin-binding domain of fibronectin drives focal adhesion formation in fibroblasts. Arch. Biochem. Biophys. 374 , 66–72 (2000).

    Article  CAS  Google Scholar 

  21. Helige, C. et al. Interrelation of motility, cytoskeletal organization and gap junctional communication with invasiveness of melanocytic cells in vitro . Invasion Metastasis 17, 26– 41 (1997).

    CAS  PubMed  Google Scholar 

  22. Maung, K., Easty, DJ., Hill, S. & Bennett, D. Requirement for focal adhesion kinase in tumor cell adhesion. Oncogene 18, 6824–6828 (1999).

    Article  CAS  Google Scholar 

  23. Silletti, S., Paku, S. & Raz, A. Autocrine motility factor and the extracellular matrix. I. Coordinate regulation of melanoma cell adhesion, spreading and migration involves focal contact reorganization. Int. J. Cancer 76, 120– 128 (1998)

    Article  CAS  Google Scholar 

  24. Duggan, D. J., Bittner, M., Chen, Y., Meltzer, P. & Trent, J. Expression profiling using cDNA microarrays. Nature Genet. 21, 10–14, (1999).

    Article  CAS  Google Scholar 

  25. Khan, J., Bittner, M., Chen, Y., Meltzer, P. & Trent, J. DNA Microarray technology: the anticipated impact on the study of human disease. Biochim. Biophys. Acta 1423, 17–28 (1999).

    Google Scholar 

  26. Tamura, M. et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280, 1614 –1617 (1998).

    Article  ADS  CAS  Google Scholar 

  27. Berens, M., Rief, M., Loo, M. & Giese, A. The role of extracellular matrix in human astrocytoma migration and proliferation studied in a microliter scale assay. Clin. Exp. Metastasis 12, 405 –415 (1994).

    Article  CAS  Google Scholar 

  28. Giese, A., Loo, M., Norman, S., Treasurywala, S. & Berens, M. Contrasting migratory response of astrocytoma cells to tenascin mediated by different integrins. J. Cell Sci. 109, 2161–8 (1996).

    Article  CAS  Google Scholar 

  29. Hendrix, M., Seftor, E., Seftor, R. & Fidler, I. A simple quantitative assay for studying the invasive potential of high and low human metastatic variants. Cancer Lett. 38, 137– 147 (1987).

    Article  CAS  Google Scholar 

  30. Hendrix, M., Seftor, E., Chu, Y., Trevor, K. & Seftor, R. Role of intermediate filaments in migration, invasion and metastasis. Cancer Metastasis Rev. 15, 507–525 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Grant support from NIH (M.E.B, M.H.) and the Australian National Health and Medical Research Council (N.H.). We thank D. Edwards for access to instrumentation used in high throughput cell migration screening; A. Cress, K. Yamada and P. Schwartzberg for discussions on cell motility and assay design; and J. Pe’er, R. Folberg, K. Daniels and J. Kan-Mitchell for donation of uveal melanoma cell lines described in ref. 5.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M. Bittner.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bittner, M., Meltzer, P., Chen, Y. et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature 406, 536–540 (2000). https://doi.org/10.1038/35020115

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35020115

This article is cited by

Comments

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.

Search

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