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

Research output: Contribution to journalArticle

Abstract

Despite of multitude investigations no reliable prognostic immunohistochemical biomark-ers 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.

Details

Authors
  • 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
Organisations
External organisations
  • University Hospital of Cologne
  • University Medical Center Göttingen
  • University of Helsinki
  • Norwegian Radium Hospital
  • Helsinki University Central Hospital
  • University Hospital Münster
  • Skåne University Hospital
  • HELIOS Klinikum Berlin-Buch
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Article numbere0193048
JournalPLoS ONE
Volume13
Issue number2
Publication statusPublished - 2018 Feb 1
Publication categoryResearch
Peer-reviewedYes