Abstract
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. 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. 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). 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.
Highlights
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract [1]
All relapsing GISTs with very low/low risk according to Fletcher showed high MAPKAPK2 and KIT expression
Patients with low-risk GISTs showing MAPKAPK2 overexpression might profit from early adjuvant tyrosine kinase inhibitor therapy
Summary
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract [1]. Radical surgery seems to be the best treatment option for localized GIST tumors [2]. The recurrence rate after radical surgery seems to depend mainly on tumor localization, size, and mitotic activity and ranges between 5% and 75%, with a poor clinical outcome in relapsed patients [3, 4]. Current classifications take into account tumor size, Authors' Affiliations: Departments of 1Surgery and 2Obstetrics and Gynecology, 3Clinical Institute of Pathology, 4Institute of Neurology, Medical University of Vienna; and 5University of Applied Sciences, FH Campus Wien, Vienna, Austria. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Mitotic rate, and tumor location, but they do not include mutational data nor protein expressions of tumor cells [5,6,7]. Due to the wide range of behavior, it is important to identify further factors providing a prognostic value in predicting the risk of relapse of fully resected tumors
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