title: Modeling genomic diversity and tumor dependency in malignant melanoma.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Lin
authors.forename: Alissa C
authors.initials: AC
authors.lastname: Baker
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.forename: Whei
authors.initials: W
authors.lastname: Feng
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Marmion
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Laine
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Hsiuyi
authors.initials: H
authors.lastname: Tseng
authors.forename: Casey
authors.initials: C
authors.lastname: Gates
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D000465:Algorithms; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002879:Chromosomes, Human, Pair 10; D016000:Cluster Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D019656:Loss of Heterozygosity; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D048490:raf Kinases / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human