title: A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number.
abstract: In addition to KIT and PDGFRA mutations, sequential accumulation of other genetic events is involved in the development and progression of gastrointestinal stromal tumors (GISTs). Until recently, the significance of these other alterations has not been thoroughly investigated. We report the first study that integrates gene expression profiling and high-resolution genomic copy number analyses in GIST. Fresh tissue specimens from 25 patients with GIST were collected, and gene expression profiling and high-resolution genomic copy number analyses were performed, using Affymetrix U133Plus and SNP array 6.0. We found that all 21 mutant GIST patients showed both macroscopic cytogenetic alterations and cryptic microdeletions or amplifications, whereas 75% (three of four) of wild-type patients with GIST did not show genomic imbalances. The most frequently observed chromosomal alterations in patients with mutant GIST included 14q complete or partial deletion (17 of 25), 1p deletion (14 of 25) and 22q deletion (10 of 25). Genetic targets of the chromosomal aberrations were selected by integrated analysis of copy number and gene expression data. We detected the involvement of known oncogenes and tumor suppressors including KRAS in chr 12p amplification and KIF1B, PPM1A, NF2 in chr 1p, 14q and 22p deletions, respectively. The genomic segment most frequently altered in mutated samples was the 14q23.1 region, which contains potentially novel tumor suppressors, including DAAM1, RTN1 and DACT1. siRNA-mediated RTN1 downregulation showed evidence for the potential role in GIST pathogenesis. The combination of gene expression profiling and high-resolution genomic copy number analysis offers a detailed molecular portrait of GISTs, providing an essential comprehensive knowledge necessary to guide the discovery of novel target genes involved in tumor development and progression.
authors.affiliation: Interdepartmental Centre for Cancer Research G. Prodi, University of Bologna, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Astolfi
authors.forename: Margherita
authors.initials: M
authors.lastname: Nannini
authors.forename: Maria Abbondanza
authors.initials: MA
authors.lastname: Pantaleo
authors.forename: Monica
authors.initials: M
authors.lastname: Di Battista
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Donatella
authors.initials: D
authors.lastname: Santini
authors.forename: Fausto
authors.initials: F
authors.lastname: Catena
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.forename: Alessandra
authors.initials: A
authors.lastname: Maleddu
authors.forename: Maristella
authors.initials: M
authors.lastname: Saponara
authors.forename: Cristian
authors.initials: C
authors.lastname: Lolli
authors.forename: Valerio
authors.initials: V
authors.lastname: Di Scioscio
authors.forename: Serena
authors.initials: S
authors.lastname: Formica
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D002892:Chromosomes, Human, Pair 22 / Q000378:metabolism; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods*; D011905:Genes, ras; D016678:Genome; D005838:Genotype; D006801:Humans; D046228:Microarray Analysis; D008840:Microfilament Proteins; D009154:Mutation; D009857:Oncogenes; D020641:Polymorphism, Single Nucleotide; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C499094:DAAM1 protein, human; D008840:Microfilament Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020741:rho GTP-Binding Proteins