A molecular portrait of gastrointestinal stromal tumors: an integrative analysis of gene expression profiling and high-resolution genomic copy number

• Published in: Laboratory investigation Vol. 90; no. 9; pp. 1285 - 1294
• Main Authors: Astolfi, Annalisa, Nannini, Margherita, Pantaleo, Maria Abbondanza, Di Battista, Monica, Heinrich, Michael C, Santini, Donatella, Catena, Fausto, Corless, Christopher L, Maleddu, Alessandra, Saponara, Maristella, Lolli, Cristian, Di Scioscio, Valerio, Formica, Serena, Biasco, Guido
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2010; Nature Publishing Group
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Biological and medical sciences; Biotechnology; Chromosome Aberrations; Chromosomes, Human, Pair 22 - metabolism; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; gastrointestinal stromal tumors; Gastrointestinal Stromal Tumors - genetics; Gastrointestinal Stromal Tumors - metabolism; Gastrointestinal Stromal Tumors - pathology; Gene Expression; gene expression profiling; Gene Expression Profiling - methods; Genes, ras; Genome; Genotype; Humans; Investigative techniques, diagnostic techniques (general aspects); Medical sciences; Microarray Analysis; Microfilament Proteins; Mutation; Oncogenes; Polymorphism, Single Nucleotide; Receptor, Platelet-Derived Growth Factor alpha - genetics; Receptor, Platelet-Derived Growth Factor alpha - metabolism; rho GTP-Binding Proteins; SNPs array; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; gene expression profiling; SNPs array; gastrointestinal stromal tumors; Biotechnology; High resolution; Copy number; Genomics; Malignant tumor; Gastrointestinal stromal tumor; Gene expression profile; Clinical biology; Genetics; Digestive diseases; Intestinal disease; Single nucleotide polymorphism; Genome; Cancer; Gastric disease
• ISSN: 0023-6837; 1530-0307
• DOI: 10.1038/labinvest.2010.110

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.