Differenzielle Regulation und prognostische Bedeutung von zellzyklusassoziierten Regulatoren der G1- und G2-Phase in Abhängigkeit von der anatomischen Lokalisation in Gastrointestinalen Stromatumoren (GIST)

Abstract

AIM: Gastrointestinal stromal tumors (GIST) belong to the most common mesenchymal GI neoplasms (70%). Generally, gastric GISTs show a more favourable clinical outcome compared to GISTs from the small intestine and large bowel equal of size and mitotic activity. The aim of the current study was to evaluate if the different clinical outcome of unlike localised GISTs is due to an anatomical differential regulation of cell cycle proteins from different phases of the cell cycle and to evaluate the prognostic significance of these clinical markers by comparison of their expression and follow-up. MATERIALS & METHODS: A series of 148 primary surgically resected GISTs was analysed by tissue-microarray-technology and immunhistochemical staining. The quantitative expression of the G1-phase-proteins E2F1 and cyclin D1, as well as of the G2-phase-proteins cyclin A2 and B1 and of the transcription factor myc were reviewed subject to the clinical-pathological parameters anatomical localisation, morphology, tumor size, mitotic count and mutational status. RESULTS: The expression of the cell cycle proteins in distinct localised KIT-mutated GISTs revealed two different patterns: E2F1 and by trend cyclin D1 as early proliferation proteins had a higher expression in KIT-mutated GISTs from the stomach and large bowel compared to tumors from the small intestine. In contrast, the late proliferation proteins cyclin A2 and B1 as well as myc acted differently and showed a higher expression in KIT-mutated GISTs from the small intestine compared to gastric GISTs. The expression of E2F1 had a significant influence on the disease-free survival after surgery in the whole cohort. On closer examination of the anatomical localisation, our results showed that E2F1 could only be used as a significant prognostic marker in KIT-mutated GISTs from the small intestine and large bowel; a distinct E2F1-expression in gastric GISTs with KIT-mutation did not lead to a different clinical outcome. Cyclin D1 and myc showed no significant correlation between the level of their expression and the length of the disease-free survival. The expression of cyclin A2 and B1 revealed a significant impact on the clinical course. CONCLUSIONS: Our findings indicate two different regulatory mechanisms for proliferation in KIT-mutated GISTs from the stomach and small intestine: cyclin D1 and E2F1 as G1-phase proteins could be priorly responsible for the cell cycle activation in gastric GISTs while myc and the S-/G2-phase proteins cyclin A2 and B1 could be mostly relevant for the cell cycle progression in GISTs from the small intestine. On the other hand, the results including the follow-up lead to the assumption that E2F1 with its higher expression in KIT-mutated gastric GISTs could rather initiate apoptosis instead of proliferation in these tumors. Thus, it could lead to a more favorable clinical outcome of gastric GISTs. As clinical prognostic markers, E2F1, cyclin A2 and B1 seem to be useful and appropriate to predict the clinical behaviour of GISTs, even if the role of E2F1 in gastric KIT-mutated GISTs needs to be further investigated. Cyclin D1 and myc do not seem to be capable prognostic markers. Though, it is conjecturable that myc takes an important position in the cell cycle of GISTs from the small intestine.