Increased KIT signalling with up-regulation of cyclin D correlates to accelerated proliferation and shorter disease-free survival in gastrointestinal stromal tumours (GISTs) with KIT exon 11 deletions.
Gastrointestinal stromal tumours (GISTs) with deletions in KIT exon 11 are characterized by higher proliferation rates and shorter disease-free survival times, compared to GISTs with KIT exon 11 point mutations. Up-regulation of cyclin D is a crucial event for entry into the G1 phase of the cell cycle, and links mitogenic signalling to cell proliferation. Signalling from activated KIT to cyclin D is directed through the RAS/RAF/ERK, PI3K/AKT/mTOR/EIF4E, and JAK/STATs cascades. ERK and STATs initiate mRNA transcription of cyclin D, whereas EIF4E activation leads to increased translation efficiency and reduced degradation of cyclin D protein. The aim of the current study was to analyse the mRNA and protein expression as well as protein phosphorylation of central hubs of these signalling cascades in primary GISTs, to evaluate whether tumours with KIT exon 11 deletions and point mutations differently utilize these pathways. GISTs with KIT exon 11 deletions had significantly higher mitotic counts, higher proliferation rates, and shorter disease-free survival times. In line with this, they had significantly higher expression of cyclin D on the mRNA and protein level. Furthermore, there was a significantly higher amount of phosphorylated ERK1/2, and a higher protein amount of STAT3, mTOR, and EIF4E. PI3K and phosphorylated AKT were also up-regulated, but this was not significant. Ultimately, GISTs with KIT exon 11 deletions had significantly higher phosphorylation of the central negative cell-cycle regulator RB. Phosphorylation of RB is accomplished by activated cyclin D/CDK4/6 complex, and marks a central event in the release of the cell cycle. Altogether, these observations suggest increased KIT signalling with up-regulation of cyclin D as the basis for the unfavourable clinical course in GISTs with KIT exon 11 deletions.
Haller
F
F
Department of Pathology, Georg August University, Göttingen, Germany. florian.haller@med.unigoettingen.de
Löbke
C
C
Ruschhaupt
M
M
Schulten
H-J
HJ
Schwager
S
S
Gunawan
B
B
Armbrust
T
T
Langer
C
C
Ramadori
G
G
Sültmann
H
H
Poustka
A
A
Korf
U
U
Füzesi
L
L
D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D005091:Exons; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D040081:Protein Array Analysis; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D015854:Up-Regulation
D056741:Cyclin D; D016213:Cyclins; D019009:Proto-Oncogene Proteins c-kit