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Cancer Res DOI:10.1158/0008-5472.CAN-07-2615

Modeling genomic diversity and tumor dependency in malignant melanoma.

Publication TypeJournal Article
Year of Publication2008
AuthorsLin, WM, Baker, AC, Beroukhim, R, Winckler, W, Feng, W, Marmion, JM, Laine, E, Greulich, H, Tseng, H, Gates, C, F Hodi, S, Dranoff, G, Sellers, WR, Thomas, RK, Meyerson, M, Golub, TR, Dummer, R, Herlyn, M, Getz, G, Garraway, LA
JournalCancer Res
Date Published2008 Feb 01
KeywordsAlgorithms, Cell Line, Tumor, Chromosome Aberrations, Chromosome Deletion, Chromosomes, Human, Pair 10, Cluster Analysis, DNA, Neoplasm, Extracellular Signal-Regulated MAP Kinases, Gene Expression Profiling, Humans, Loss of Heterozygosity, Melanoma, Mitogen-Activated Protein Kinases, Polymorphism, Single Nucleotide, PTEN Phosphohydrolase, raf Kinases, Receptor, Fibroblast Growth Factor, Type 1

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.


Alternate JournalCancer Res.
PubMed ID18245465
Grant ListR01 CA085912 / CA / NCI NIH HHS / United States
K08CA115927 / CA / NCI NIH HHS / United States
K08 CA122833-01A1 / CA / NCI NIH HHS / United States
K08 CA122833 / CA / NCI NIH HHS / United States
K08 CA115927 / CA / NCI NIH HHS / United States
P50CA93683 / CA / NCI NIH HHS / United States