Gastrointestinal stromal tumors (GISTs) with KIT and PDGFRA mutations have distinct gene expression profiles.
Most GISTs require oncogenic activation of the KIT or PDGFRA receptor tyrosine kinase proteins, and the genomic mechanisms of oncogene activation are heterogeneous. Notably, the kinase mutation type correlates with both tumor biology and imatinib response. For example, GISTs with KIT exon 11 mutations are typically gastric and have excellent imatinib response, whereas those with KIT exon 9 mutations generally arise in the small bowel and are less responsive to imatinib. To identify genes that might contribute to these biological differences, we carried out gene expression profiling of 26 GISTs with known KIT and PDGFRA mutational status. Expression differences were then evaluated further by RNA in situ hybridization, immunohistochemistry, and immunoblotting. Unsupervised hierarchical clustering grouped tumors with similar mutations together, but the distinction between the different groups was not absolute. Differentially expressed genes included ezrin, p70S6K, and PKCs, which are known to have key roles in KIT or PDGFRA signaling, and which might therefore contribute to the distinctive clinicopathological features in GISTs with different mutation types. These gene products could serve as highly selective therapeutic targets in GISTs containing the KIT or PDGFRA mutational types with which they are associated.
Department of Pathology, Stanford University Medical Center, Stanford, CA 94305, USA.
Subbaya
S
Subramanian
Robert B
RB
West
Christopher L
CL
Corless
Wenbin
W
Ou
Brian P
BP
Rubin
Kent-Man
KM
Chu
Suet Yi
SY
Leung
Siu Tsan
ST
Yuen
Shirley
S
Zhu
Tina
T
Hernandez-Boussard
Kelli
K
Montgomery
Torsten O
TO
Nielsen
Rajiv M
RM
Patel
John R
JR
Goldblum
Michael C
MC
Heinrich
Jonathan A
JA
Fletcher
Matt
M
van de Rijn
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics; D008297:Male; D015513:Oncogene Proteins / Q000235:genetics*; D009857:Oncogenes; D010750:Phosphoproteins / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics; D017154:Stromal Cells / Q000473:pathology*; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D015513:Oncogene Proteins; D010750:Phosphoproteins; D011493:Protein Kinase C; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000099149:Ezrin