Modeling genomic diversity and tumor dependency in malignant melanoma.

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.

[1]  David G. Stork,et al.  Pattern Classification , 1973 .

[2]  L. J. Veer,et al.  N-ras mutations in human cutaneous melanoma from sun-exposed body sites , 1989, Molecular and cellular biology.

[3]  N-ras mutations in human cutaneous melanoma from sun-exposed body sites , 1989 .

[4]  J. Kirkwood,et al.  Homozygous deletions within human chromosome band 9p21 in melanoma. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[5]  W. Clark,et al.  Germline p16 mutations in familial melanoma , 1994, Nature Genetics.

[6]  M. Skolnick,et al.  A cell cycle regulator potentially involved in genesis of many tumor types. , 1994, Science.

[7]  Edward T Kipreos,et al.  cul-1 Is Required for Cell Cycle Exit in C. elegans and Identifies a Novel Gene Family , 1996, Cell.

[8]  P. Polakis,et al.  IQGAP1, a calmodulin‐binding protein with a rasGAP‐related domain, is a potential effector for cdc42Hs. , 1996, The EMBO journal.

[9]  R. Klausner,et al.  The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S. Bhattacharya,et al.  Lineage-specific Signaling in Melanocytes , 1998, The Journal of Biological Chemistry.

[11]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Klausner,et al.  Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  David G. Stork,et al.  Pattern Classification (2nd ed.) , 1999 .

[14]  Eric S. Lander,et al.  Loss-of-heterozygosity analysis of small-cell lung carcinomas using single-nucleotide polymorphism arrays , 2000, Nature Biotechnology.

[15]  F. Haluska,et al.  Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. , 2000, Cancer research.

[16]  S. Friedman,et al.  KLF6, a Candidate Tumor Suppressor Gene Mutated in Prostate Cancer , 2001, Science.

[17]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[19]  A. D. Van den Abbeele,et al.  Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. , 2002, The New England journal of medicine.

[20]  P. Pollock,et al.  PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines , 2002, Melanoma research.

[21]  B. Weber,et al.  Cancer genomics , 2002 .

[22]  M. Baccarani,et al.  Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. , 2002, The New England journal of medicine.

[23]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[24]  Emmanuel Barillot,et al.  Analysis of array CGH data: from signal ratio to gain and loss of DNA regions , 2004, Bioinform..

[25]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[26]  Luc Girard,et al.  An integrated view of copy number and allelic alterations in the cancer genome using single nucleotide polymorphism arrays. , 2004, Cancer research.

[27]  M. Pierotti,et al.  BRAF alterations are associated with complex mutational profiles in malignant melanoma , 2004, Oncogene.

[28]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[29]  F. Haluska,et al.  Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. , 2004, The Journal of investigative dermatology.

[30]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[31]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[32]  Markus Ringnér,et al.  Microarray expression profiling in melanoma reveals a BRAF mutation signature , 2004, Oncogene.

[33]  S. Friedman,et al.  Suppression of glioblastoma tumorigenicity by the Kruppel-like transcription factor KLF6 , 2004, Oncogene.

[34]  M. Shapero,et al.  High-resolution analysis of DNA copy number using oligonucleotide microarrays. , 2004, Genome research.

[35]  S. Friedman,et al.  Frequent inactivation of the tumor suppressor Kruppel‐like factor 6 (KLF6) in hepatocellular carcinoma , 2004, Hepatology.

[36]  J. Fridlyand,et al.  Distinct sets of genetic alterations in melanoma. , 2005, The New England journal of medicine.

[37]  T. Golub,et al.  Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma , 2005, Nature.

[38]  H. Dressman,et al.  Genomic signatures to guide the use of chemotherapeutics , 2006, Nature Medicine.

[39]  Wing Hung Wong,et al.  Inferring Loss-of-Heterozygosity from Unpaired Tumors Using High-Density Oligonucleotide SNP Arrays , 2006, PLoS Comput. Biol..

[40]  L. Chin,et al.  Malignant melanoma: genetics and therapeutics in the genomic era. , 2006, Genes & development.

[41]  Paul A Clemons,et al.  The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease , 2006, Science.

[42]  J. Nevins,et al.  Linking oncogenic pathways with therapeutic opportunities , 2006, Nature Reviews Cancer.

[43]  R. Figlin,et al.  Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  S. Mukherjee,et al.  A genomic strategy to refine prognosis in early-stage non-small-cell lung cancer. , 2006, The New England journal of medicine.

[45]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[46]  J. Mesirov,et al.  GenePattern 2.0 , 2006, Nature Genetics.

[47]  John Quackenbush.  Microarray analysis and tumor classification. , 2006, The New England journal of medicine.

[48]  Todd R. Golub,et al.  BRAF mutation predicts sensitivity to MEK inhibition , 2006, Nature.

[49]  Wen-Lin Kuo,et al.  A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. , 2006, Cancer cell.

[50]  Derek Y. Chiang,et al.  Characterizing the cancer genome in lung adenocarcinoma , 2007, Nature.

[51]  M. Ringnér,et al.  Genomic profiling of malignant melanoma using tiling-resolution arrayCGH , 2007, Oncogene.

[52]  E. Lander,et al.  Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma , 2007, Proceedings of the National Academy of Sciences.

[53]  S. Gabriel,et al.  High-throughput oncogene mutation profiling in human cancer , 2007, Nature Genetics.

[54]  N. Hayward,et al.  Genome-wide loss of heterozygosity and copy number analysis in melanoma using high-density single-nucleotide polymorphism arrays. , 2007, Cancer research.

[55]  T. Golub,et al.  Malignant Melanoma Modeling Genomic Diversity and Tumor Dependency in Updated , 2008 .