title: Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma.
abstract: Cancer genomes frequently contain somatic copy number alterations (SCNA) that can significantly perturb the expression level of affected genes and thus disrupt pathways controlling normal growth. In melanoma, many studies have focussed on the copy number and gene expression levels of the BRAF, PTEN and MITF genes, but little has been done to identify new genes using these parameters at the genome-wide scale. Using karyotyping, SNP and CGH arrays, and RNA-seq, we have identified SCNA affecting gene expression ('SCNA-genes') in seven human metastatic melanoma cell lines. We showed that the combination of these techniques is useful to identify candidate genes potentially involved in tumorigenesis. Since few of these alterations were recurrent across our samples, we used a protein network-guided approach to determine whether any pathways were enriched in SCNA-genes in one or more samples. From this unbiased genome-wide analysis, we identified 28 significantly enriched pathway modules. Comparison with two large, independent melanoma SCNA datasets showed less than 10% overlap at the individual gene level, but network-guided analysis revealed 66% shared pathways, including all but three of the pathways identified in our data. Frequently altered pathways included WNT, cadherin signalling, angiogenesis and melanogenesis. Additionally, our results emphasize the potential of the EPHA3 and FRS2 gene products, involved in angiogenesis and migration, as possible therapeutic targets in melanoma. Our study demonstrates the utility of network-guided approaches, for both large and small datasets, to identify pathways recurrently perturbed in cancer.
authors.affiliation: Ludwig Institute for Cancer Research, Lausanne, Switzerland.
authors.forename: Armand
authors.initials: A
authors.lastname: Valsesia
authors.forename: Donata
authors.initials: D
authors.lastname: Rimoldi
authors.forename: Danielle
authors.initials: D
authors.lastname: Martinet
authors.forename: Mark
authors.initials: M
authors.lastname: Ibberson
authors.forename: Paola
authors.initials: P
authors.lastname: Benaglio
authors.forename: Manfredo
authors.initials: M
authors.lastname: Quadroni
authors.forename: Patrice
authors.initials: P
authors.lastname: Waridel
authors.forename: Muriel
authors.initials: M
authors.lastname: Gaillard
authors.forename: Mireille
authors.initials: M
authors.lastname: Pidoux
authors.forename: Blandine
authors.initials: B
authors.lastname: Rapin
authors.forename: Carlo
authors.initials: C
authors.lastname: Rivolta
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.forename: Andrew J G
authors.initials: AJ
authors.lastname: Simpson
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: C Victor
authors.initials: CV
authors.lastname: Jongeneel
authors.forename: Christian
authors.initials: C
authors.lastname: Iseli
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Stevenson
mesh_terms: D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations / Q000235:genetics*; D030541:Databases, Genetic; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2