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Gene Expression in Gastrointestinal Stromal Tumors Is Distinguished by KIT Genotype and Anatomic Site
Ist Teil von
Clinical cancer research, 2004-05, Vol.10 (10), p.3282-3290
Ort / Verlag
Philadelphia, PA: American Association for Cancer Research
Erscheinungsjahr
2004
Quelle
MEDLINE
Beschreibungen/Notizen
Purpose: 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.
Experimental Design: 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.