Transkriptionsanalytische und immunhistochemische Untersuchung zellzyklusassoziierter Gene in Gastrointestinalen Stromatumoren unter besonderer Berücksichtigung des prädiktiven Werts von Cyclin H

Abstract

Background: Lacking better indicators, risk estimation of gastrointestinal stromal tumors (GIST) is still based on tumor size and mitotic rate. The indication for adjuvant treatment of patients with high risk GIST after R0 resection is a controversial issue, since these patients represent a highly heterogeneous population. Therefore, the discovery of additional prognostic markers is of great importance. Aim of the work in hand is to find new indicators by investigating the cyclin-cdk-system as well as the MAPK- and p53-signaling pathways. Methods: In order to detect expression-alterations in the large number of GIST-signaling associated genes, quantitative real-time PCRs (qRT-PCR) of 16 tissue samples were conducted. After evaluation of the results cyclin H was selected for further investigation: Its expression and prognostic value was examined in a single center cohort of 92 GIST patients by immunochemical staining. Results: The qRT-PCRs showed increased transcription levels for several cyclins (A2, B1, B2, E1, H) in the course of tumor progression as well as in tumors with high risk grading. In contrast to these findings, the transcription of inhibitors of the cyclin-cdk-system (CDKN1B & C, CDKN2A & B, RKCA) was reduced. The classification of the immunohistochemistry cohort (n = 92) revealed the following distribution: 41.1% high, 21.1% intermediate, 22.2% low and 15.5% very low risk GIST. In patients with high risk GIST, the expression of cyclin H was highly predictive for reduced disease-specific survival (p = 0.032). A combination of cyclin H expression status and high risk classification yielded the strongest prognostic value for disease-specific and disease-free survival (p kleiner/gleich 0.001). Conclusion: Our data suggest that the cyclin-cdk-system may play an important role in GIST pathophysiology. Moreover, in addition to high risk classification, cyclin H expression might be an indicator for "very-high risk" GIST.