TY - JOUR
T1 - A molecular portrait of gastrointestinal stromal tumors
T2 - An integrative analysis of gene expression profiling and high-resolution genomic copy number
AU - Astolfi, Annalisa
AU - Nannini, Margherita
AU - Pantaleo, Maria Abbondanza
AU - Di Battista, Monica
AU - Heinrich, Michael C.
AU - Santini, Donatella
AU - Catena, Fausto
AU - Corless, Christopher L.
AU - Maleddu, Alessandra
AU - Saponara, Maristella
AU - Lolli, Cristian
AU - Di Scioscio, Valerio
AU - Formica, Serena
AU - Biasco, Guido
N1 - Funding Information:
Research programs on GISTs are supported by Fondazione Cassa di Risparmio of Bologna (CARISBO), Fondazione Giuseppe Alazio, Palermo, and Vanini-Cavagnino grant. This research was also supported in part by A VA Merit Review grant (MCH) and funding from the Life Raft Group (MCH).
PY - 2010/9
Y1 - 2010/9
N2 - 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.
AB - 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.
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U2 - 10.1038/labinvest.2010.110
DO - 10.1038/labinvest.2010.110
M3 - Article
C2 - 20548289
AN - SCOPUS:77956258069
SN - 0023-6837
VL - 90
SP - 1285
EP - 1294
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 9
ER -