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Modeling Genomic Diversity and Tumor Dependency in Malignant Melanoma

Departments of ¹ Medical Oncology and ² Pediatric Oncology and ³ Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School; ⁴ Department of Pathology, Harvard Medical School, Boston, Massachusetts; ⁵ The Broad Institute of M.I.T. and Harvard; ⁶ Novartis Institutes for Biomedical Research, Cambridge, Massachusetts; ⁷ Cancer Biology Division, Wistar Institute, Philadelphia, Pennsylvania; ⁸ Department of Dermatology, University of Zurich Hospital, Zürich, Switzerland; ⁹ Max Planck Institute for Neurological Research with Klaus Joachim Zulch Laboratories of the Max Planck Society and the Medical Faculty of the University of Cologne; and ¹⁰ Center for Integrated Oncology and Department I for Internal Medicine, University of Cologne, Cologne, Germany

Requests for reprints: Levi A. Garraway, Department of Medical Oncology, Dana-Farber Cancer Institute, D1542, Boston, MA 02115. Phone: 617-632-6689; E-mail: levi_garraway{at}dfci.harvard.edu.

Key Words: melanoma • genomics • microarrays • BRAF • PTEN • MEK • MAP kinase

The classification of human tumors based on molecular criteria offers tremendous clinical potential; however, discerning critical and "druggable" effectors on a large scale will also require robust experimental models reflective of tumor genomic diversity. Here, we describe a comprehensive genomic analysis of 101 melanoma short-term cultures and cell lines. Using an analytic approach designed to enrich for putative "driver" events, we show that cultured melanoma cells encompass the spectrum of significant genomic alterations present in primary tumors. When annotated according to these lesions, melanomas cluster into subgroups suggestive of distinct oncogenic mechanisms. Integrating gene expression data suggests novel candidate effector genes linked to recurrent copy gains and losses, including both phosphatase and tensin homologue (PTEN)–dependent and PTEN-independent tumor suppressor mechanisms associated with chromosome 10 deletions. Finally, sample-matched pharmacologic data show that FGFR1 mutations and extracellular signal–regulated kinase (ERK) activation may modulate sensitivity to mitogen-activated protein kinase/ERK kinase inhibitors. Genetically defined cell culture collections therefore offer a rich framework for systematic functional studies in melanoma and other tumors. [Cancer Res 2008;68(3):664–73]