Functional features of gene expression profiles differentiating gastrointestinal stromal tumours according to KIT mutations and expression.
BACKGROUND
Gastrointestinal stromal tumours (GISTs) represent a heterogeneous group of tumours of mesenchymal origin characterized by gain-of-function mutations in KIT or PDGFRA of the type III receptor tyrosine kinase family. Although mutations in either receptor are thought to drive an early oncogenic event through similar pathways, two previous studies reported the mutation-specific gene expression profiles. However, their further conclusions were rather discordant. To clarify the molecular characteristics of differentially expressed genes according to GIST receptor mutations, we combined microarray-based analysis with detailed functional annotations.


METHODS
Total RNA was isolated from 29 frozen gastric GISTs and processed for hybridization on GENECHIP HG-U133 Plus 2.0 microarrays (Affymetrix). KIT and PDGFRA were analyzed by sequencing, while related mRNA levels were analyzed by quantitative RT-PCR.


RESULTS
Fifteen and eleven tumours possessed mutations in KIT and PDGFRA, respectively; no mutation was found in three tumours. Gene expression analysis identified no discriminative profiles associated with clinical or pathological parameters, even though expression of hundreds of genes differentiated tumour receptor mutation and expression status. Functional features of genes differentially expressed between the two groups of GISTs suggested alterations in angiogenesis and G-protein-related and calcium signalling.


CONCLUSIONS
Our study has identified novel molecular elements likely to be involved in receptor-dependent GIST development and allowed confirmation of previously published results. These elements may be potential therapeutic targets and novel markers of KIT mutation status.
Ostrowski
Jerzy
J
Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland. jostrow@warman.com.pl
Polkowski
Marcin
M
Paziewska
Agnieszka
A
Skrzypczak
Magdalena
M
Goryca
Krzysztof
K
Rubel
Tymon
T
Kokoszyñska
Katarzyna
K
Rutkowski
Piotr
P
Nowecki
Zbigniew I
ZI
Vel Dobosz
Anna Jerzak
AJ
Jarosz
Dorota
D
Ruka
Wlodzimierz
W
Wyrwicz
Lucjan S
LS
D014408:Biomarkers, Tumor / Q000032:analysis*; D004252:DNA Mutational Analysis; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000145:classification* / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha