Universität zu Köln

Ihle, Michaela Angelika, Huss, Sebastian, Jeske, Wiebke, Hartmann, Wolfgang ORCID: 0000-0002-7609-5021, Merkelbach-Bruse, Sabine, Schildhaus, Hans-Ulrich, Buettner, Reinhard, Sihto, Harri, Hall, Kirsten Sundby, Eriksson, Mikael, Reichardt, Peter, Joensuu, Heikki ORCID: 0000-0003-0281-2507 and Wardelmann, Eva (2018). Expression of cell cycle regulators and frequency of TP53 mutations in high risk gastrointestinal stromal tumors prior to adjuvant imatinib treatment. PLoS One, 13 (2). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ihle, Michaela Angelika UNSPECIFIED UNSPECIFIED UNSPECIFIED Huss, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Jeske, Wiebke UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Wolfgang UNSPECIFIED orcid.org/0000-0002-7609-5021 UNSPECIFIED Merkelbach-Bruse, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Schildhaus, Hans-Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Sihto, Harri UNSPECIFIED UNSPECIFIED UNSPECIFIED Hall, Kirsten Sundby UNSPECIFIED UNSPECIFIED UNSPECIFIED Eriksson, Mikael UNSPECIFIED UNSPECIFIED UNSPECIFIED Reichardt, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Joensuu, Heikki UNSPECIFIED orcid.org/0000-0003-0281-2507 UNSPECIFIED Wardelmann, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-195905
DOI:	10.1371/journal.pone.0193048
Journal or Publication Title:	PLoS One
Volume:	13
Number:	2
Date:	2018
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1932-6203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language P53 GENE-MUTATIONS; MUTANT P53; PROGNOSTIC-SIGNIFICANCE; BREAST-CANCER; PROTEIN OVEREXPRESSION; WILD-TYPE; IN-VIVO; SARCOMA; GISTS; CDK4 Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19590