RT Journal Article
SR Electronic
T1 Novel Clinically Relevant Genes in Gastrointestinal Stromal Tumors Identified by Exome Sequencing
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5329
OP 5339
DO 10.1158/1078-0432.CCR-12-3863
VO 19
IS 19
A1 Schoppmann, Sebastian F.
A1 Vinatzer, Ursula
A1 Popitsch, Niko
A1 Mittlböck, Martina
A1 Liebmann-Reindl, Sandra
A1 Jomrich, Gerd
A1 Streubel, Berthold
A1 Birner, Peter
YR 2013
UL http://clincancerres.aacrjournals.org/content/19/19/5329.abstract
AB Purpose: 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. Material and Methods: A cohort of 174 GIST was investigated using DNA array (n = 29), FISH (n = 125), exome sequencing (n = 13), and immunohistochemistry (n = 145). Results: 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. Conclusion: 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. Clin Cancer Res; 19(19); 5329–39. ©2013 AACR.