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MAPKAP kinase 2 overexpression influences prognosis in gastrointestinal stromal tumors and associates with copy number variations on chromosome 1 and expression of p38 MAP kinase and ETV1.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2012 Apr 01; Vol. 18 (7), pp. 1879-87. Date of Electronic Publication: 2012 Feb 20. - Publication Year :
- 2012
-
Abstract
- Purpose: ETV1 has been proposed to be activated by KIT mutations in gastrointestinal stromal tumors (GIST). The aim of the study was to evaluate the clinical role of ETV1 and associated proteins in GIST.<br />Experimental Design: Expressions of ETV1, MAPKAP kinase 2 (MAPKAPK2), phosphorylated p38 MAP kinase (pp38), phosphorylated MSK1 (pMSK1), phosphorylated RSK1, COP1, and KIT protein were determined immunohistochemically in 139 GISTs. Sequence analysis of KIT, PDGFRA, and MAPKAPK2 and FISHs of ETV1 as well as chromosomes 1 and 7 were done.<br />Results: Prominent ETV1 expression was seen in 50% of GISTs, but no correlation with clinical outcome was found. Correlation of ETV1 expression and KIT mutation was seen in 60% of cases. MAPKAPK2 overexpression (n = 62/44.6%) correlated with pp38 expression (P = 0.021, χ(2) test) and alterations of chromosome 1 (n = 17, P = 0.024, χ(2) test). In one of 20 sequenced cases with high MAKAPK2 expression, a putative damaging MAPKAPK2 gene mutation was found. All relapsing GISTs with very low/low risk according to Fletcher showed high MAPKAPK2 and KIT expression. MAPKAPK2 overexpression was an independent prognostic factor for disease-free survival (P = 0.006, Cox regression).<br />Conclusion: ETV1 is not universally overexpressed in GIST and seems to also be induced by pathways other than KIT mutation. Nevertheless, its clinical relevance is low. Overexpression of ETV1 inhibitor MAPKAPK2 is associated with shorter survival in GIST, indicating a clinically relevant role of this gene not reported previously. Patients with low-risk GISTs showing MAPKAPK2 overexpression might profit from early adjuvant tyrosine kinase inhibitor therapy.<br /> (©2012 AACR.)
- Subjects :
- Aged
DNA-Binding Proteins metabolism
Female
Gastrointestinal Stromal Tumors diagnosis
Gastrointestinal Stromal Tumors metabolism
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Intracellular Signaling Peptides and Proteins metabolism
Kaplan-Meier Estimate
Male
Microscopy, Confocal
Middle Aged
Mutation
Prognosis
Protein Serine-Threonine Kinases metabolism
Ribosomal Protein S6 Kinases, 90-kDa genetics
Ribosomal Protein S6 Kinases, 90-kDa metabolism
Transcription Factors metabolism
Ubiquitin-Protein Ligases genetics
Ubiquitin-Protein Ligases metabolism
p38 Mitogen-Activated Protein Kinases metabolism
Chromosomes, Human, Pair 1 genetics
DNA Copy Number Variations
DNA-Binding Proteins genetics
Gastrointestinal Stromal Tumors genetics
Intracellular Signaling Peptides and Proteins genetics
Protein Serine-Threonine Kinases genetics
Transcription Factors genetics
p38 Mitogen-Activated Protein Kinases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 18
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 22351694
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-11-2364