This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lin, W. M. Articles by Garraway, L. A. Search for Related Content PubMed PubMed Citation Articles by Lin, W. M. Articles by Garraway, L. A.

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]

This article has been cited by other articles:

				K. Schad, K. Baumann Conzett, M. C. Zipser, V. Enderlin, J. Kamarashev, L. E. French, and R. Dummer Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibition Results in Biphasic Alteration of Epidermal Homeostasis with Keratinocytic Apoptosis and Pigmentation Disorders Clin. Cancer Res., February 1, 2010; 16(3): 1058 - 1064. [Abstract] [Full Text] [PDF]

				C. M. Emery, K. G. Vijayendran, M. C. Zipser, A. M. Sawyer, L. Niu, J. J. Kim, C. Hatton, R. Chopra, P. A. Oberholzer, M. B. Karpova, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition PNAS, December 1, 2009; 106(48): 20411 - 20416. [Abstract] [Full Text] [PDF]

				I. K. Guttilla and B. A. White Coordinate Regulation of FOXO1 by miR-27a, miR-96, and miR-182 in Breast Cancer Cells J. Biol. Chem., August 28, 2009; 284(35): 23204 - 23216. [Abstract] [Full Text] [PDF]

				B. Modrek, L. Ge, A. Pandita, E. Lin, S. Mohan, P. Yue, S. Guerrero, W. M. Lin, T. Pham, Z. Modrusan, et al. Oncogenic Activating Mutations Are Associated with Local Copy Gain Mol. Cancer Res., August 1, 2009; 7(8): 1244 - 1252. [Abstract] [Full Text] [PDF]

				P. Hersey, L. Bastholt, V. Chiarion-Sileni, G. Cinat, R. Dummer, A. M. M. Eggermont, E. Espinosa, A. Hauschild, I. Quirt, C. Robert, et al. Small molecules and targeted therapies in distant metastatic disease Ann. Onc., August 1, 2009; 20(suppl_6): vi35 - vi40. [Abstract] [Full Text] [PDF]

				D. M. Su, Q. Zhang, X. Wang, P. He, Y. J. Zhu, J. Zhao, O. M. Rennert, and Y. A. Su Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy Mol. Cancer Ther., May 1, 2009; 8(5): 1292 - 1304. [Abstract] [Full Text] [PDF]

				K. S.M. Smalley, K. L. Nathanson, and K. T. Flaherty Genetic Subgrouping of Melanoma Reveals New Opportunities for Targeted Therapy Cancer Res., April 15, 2009; 69(8): 3241 - 3244. [Abstract] [Full Text] [PDF]

				M. F. Segura, D. Hanniford, S. Menendez, L. Reavie, X. Zou, S. Alvarez-Diaz, J. Zakrzewski, E. Blochin, A. Rose, D. Bogunovic, et al. Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor PNAS, February 10, 2009; 106(6): 1814 - 1819. [Abstract] [Full Text] [PDF]

				C. Beadling, E. Jacobson-Dunlop, F. S. Hodi, C. Le, A. Warrick, J. Patterson, A. Town, A. Harlow, F. Cruz III, S. Azar, et al. KIT Gene Mutations and Copy Number in Melanoma Subtypes Clin. Cancer Res., November 1, 2008; 14(21): 6821 - 6828. [Abstract] [Full Text] [PDF]

				A. Sekulic, P. Haluska Jr, A. J. Miller, J. G. De Lamo, S. Ejadi, J. S. Pulido, D. R. Salomao, E. C. Thorland, R. G. Vile, D. L. Swanson, et al. Malignant Melanoma in the 21st Century: The Emerging Molecular Landscape Mayo Clin. Proc., July 1, 2008; 83(7): 825 - 846. [Abstract] [Full Text] [PDF]