Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site.
OBJECTIVE
Gastrointestinal stromal tumors (GISTs) are specific KIT expressing and KIT-signaling driven mesenchymal tumors of the human digestive tract, many of which have KIT-activating mutations. Previous studies have found a relatively homogeneous gene expression profile in GIST, as compared with other histological types of sarcomas. Transcriptional heterogeneity within clinically or molecularly defined subsets of GISTs has not been previously reported. We tested the hypothesis that the gene expression profile in GISTs might be related to KIT genotype and possibly to other clinicopathological factors.


METHODS
An HG-U133A Affymetrix chip (22,000 genes) platform was used to determine the variability of gene expression in 28 KIT-expressing GIST samples from 24 patients. A control group of six intra-abdominal leiomyosarcomas was also included for comparison. Statistical analyses (t tests) were performed to identify discriminatory gene lists among various GIST subgroups. The levels of expression of various GIST subsets were also linked to a modified version of the growth factor/KIT signaling pathway to analyze differences at various steps in signal transduction.


RESULTS
Genes involved in KIT signaling were differentially expressed among wild-type and mutant GISTs. High gene expression of potential drug targets, such as VEGF, MCSF, and BCL2 in the wild-type group, and Mesothelin in exon 9 GISTs were found. There was a striking difference in gene expression between stomach and small bowel GISTs. This finding was validated in four separate tumors, two gastric and two intestinal, from a patient with familial GIST with a germ-line KIT W557R substitution.


CONCLUSIONS
GISTs have heterogeneous gene expression depending on KIT genotype and tumor location, which is seen at both the genomic level and the KIT signaling pathway in particular. These findings may explain their variable clinical behavior and response to therapy.
Antonescu
Cristina R
CR
Departments of Pathology, Memorial Sloan-Kettering Cancer Center, and Molecular Biology, Computational Biology Center, Sloan-Kettering Institute, New York, New York 10021, USA. antonesc@mskcc.org
Viale
Agnes
A
Sarran
Lisa
L
Tschernyavsky
Sylvia J
SJ
Gonen
Mithat
M
Segal
Neil H
NH
Maki
Robert G
RG
Socci
Nicholas D
ND
DeMatteo
Ronald P
RP
Besmer
Peter
P
D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005091:Exons; D005753:Gastric Mucosa / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007421:Intestine, Small / Q000378:metabolism; D009154:Mutation; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D006133:Growth Substances; D042461:Vascular Endothelial Growth Factor A; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor