Abstract
Chromosomal gains and losses resulting in altered gene dosage are known to be recurrent in gastrointestinal stromal tumors (GIST). The aim of our study was the identification of clinical relevant genes in these candidate regions. A cohort of 174 GIST was investigated using DNA array (n = 29), FISH (n = 125), exome sequencing (n = 13), and immunohistochemistry (n = 145). Array analysis revealed recurrent copy number variations (CNVs) of chromosomal arms 1p, 1q, 3p, 4q, 5q, 7p, 11q, 12p, 13q, 14q, 15q, and 22q. FISH studies of these CNVs showed that relative loss of 1p was associated with shorter disease-free survival (DFS). Analysis of exome sequencing concentrating on target regions showing recurrent CNVs revealed a median number of 3,404 (range 1,641-13,602) variants (SNPs, insertions, deletions) in each tumor minus paired blood sample; variants in at least three samples were observed in 37 genes. After further analysis, target genes were reduced to 10 in addition to KIT and PDGFRA. Immunohistochemical investigation showed that expression of SYNE2 and DIAPH1 was associated with shorter DFS, expression of RAD54L2 with shorter and expression of KIT with longer overall survival. Using a novel approach combining DNA arrays, exome sequencing, and immunohistochemistry, we were able to identify 10 target genes in GIST, of which three showed hithero unknown clinical relevance. Because the identified target genes SYNE2, MAPK8IP2, and DIAPH1 have been shown to be involved in MAP kinase signaling, our data further indicate the important role of this pathway in GIST.
Highlights
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract [1]
Because a part of the identified target genes has been shown to be involved in MAP kinase signaling, our data further indicate the important role of this pathway in GIST
The microarray platform used allows for the detection of copy number variations (CNVs) down to 50 kb or smaller, we aimed to assess the minimal region of overlap of recurrent genomic regions that are known to be much larger
Summary
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract [1] They are thought to arise from Cajal cells or their precursors and characteristically harbor gain of function mutations in KIT leading to constitutive activation of the KIT receptor [2]. Effectiveness of imatinib mesylate depends on the mutational status of KIT and PDGFRA [3]. In contrast to metastatic GIST, radical surgery seems to be the best treatment option for localized tumors [6]. The recurrence rate after radical surgery seems to depend mainly on tumor localization, size, and mitotic activity and ranges between 5% and 75% with a poor clinical outcome in relapsed patients [7, 8]. Current classifications take into account tumor size, mitotic rate, and tumor location but do not include mutational data nor protein expressions of tumor cells [9,10,11]
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