Research Article: Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment

Date Published: February 16, 2018

Publisher: Public Library of Science

Author(s): Michaela Angelika Ihle, Sebastian Huss, Wiebke Jeske, Wolfgang Hartmann, Sabine Merkelbach-Bruse, Hans-Ulrich Schildhaus, Reinhard Büttner, Harri Sihto, Kirsten Sundby Hall, Mikael Eriksson, Peter Reichardt, Heikki Joensuu, Eva Wardelmann, Anette Duensing.


Despite of multitude investigations no reliable prognostic immunohistochemical biomarkers in GIST have been established so far with added value to predict the recurrence risk of high risk GIST besides mitotic count, primary location and size. In this study, we analyzed the prognostic relevance of eight cell cycle and apoptosis modulators and of TP53 mutations for prognosis in GIST with high risk of recurrence prior to adjuvant treatment with imatinib. In total, 400 patients with high risk for GIST recurrence were randomly assigned for adjuvant imatinib either for one or for three years following laparotomy. 320 primary tumor samples with available tumor tissue were immunohistochemically analyzed prior to treatment for the expression of cell cycle regulators and apoptosis modulators cyclin D1, p21, p16, CDK4, E2F1, MDM2, p53 and p-RB1. TP53 mutational analysis was possible in 245 cases. A high expression of CDK4 was observed in 32.8% of all cases and was associated with a favorable recurrence free survival (RFS), whereas high expression of MDM2 (12.2%) or p53 (35.3%) was associated with a shorter RFS. These results were independent from the primary KIT or PDGFRA mutation. In GISTs with higher mitotic counts was a significantly increased expression of cyclin D1, p53 and E2F1. The expression of p16 and E2F1 significantly correlated to a non-gastric localization. Furthermore, we observed a significant higher expression of p21 and E2F1 in KIT mutant GISTs compared to PDGFRA mutant and wt GISTs. The overall frequency of TP53 mutations was low (n = 8; 3.5%) and could not be predicted by the immunohistochemical expression of p53. In summary, mutation analysis in TP53 plays a minor role in the subgroup of high-risk GIST before adjuvant treatment with imatinib. Strong expression of MDM2 and p53 correlated with a shorter recurrence free survival, whereas a strong expression of CDK4 correlated to a better recurrence free survival.

Partial Text

95% of gastrointestinal stromal tumors (GIST) exhibit an overexpression of the receptor tyrosine kinase KIT [1]. Approximately 90% harbor a mutation in the KIT gene or in the gene of the homolog receptor tyrosine kinase PDGFRA. These mutations lead to ligand independent, constitutive activation of the kinases and play a central role in GIST development [2]. A minority of GIST without gain-of-function mutations in one of these two kinases display other genetic and epigenetic changes [3–5]. These alterations are located in the BRAF (rapidly accelerated fibrosarcoma B) gene, in the succinate dehydrogenase (SDH) complex or the insulin-like growth factor 1 receptor (IGF1R) gene [6]. Furthermore, Hur et al. showed that especially genes of the cell cycle control are altered in high risk compared to low risk GIST [7]. One such gene is TP53 encoding a 64 kDa protein (p53). Its gene product p53 is an essential regulator of many genes controlling apoptosis, senescence, DNA damage repair and cell cycle arrest [1]. Upon radiation-induced damage, p53 is activated as an element of the G1-phase checkpoint to allow DNA repair. Activation of p53 leads to the induction of p21 (CDKN2A) that binds to and inactivates cyclin-dependent kinases (CDK) complexed with cyclins’ (cyclin = CCN: cyclin D1/CDK4, cyclin D1/CDK6 and cyclin E1/CDK2). Consequently, the cell cycle is arrested [8]. Without this p21-induced inhibition complexed CDKs and cyclins phosphorylate the retinoblastoma 1 (RB1) protein that dissociates from E2F1 transcription factor. As a result transcriptional activation of a series of target genes leads to the progression of the cell cycle.

In this study, we demonstrated that a high expression of CDK4 was surprisingly associated with a favorable recurrence free survival (RFS), whereas a high expression of MDM2 or p53 (TP53) was associated with unfavorable RFS. These results were independent from the underlying primary KIT or PDGFRA mutation.




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