MET-Alterationen als therapeutisches Target bei metastasierten kolorektalen KarzinomenDoctoral thesis
Date of Examination:2024-02-06
Date of issue:2024-02-09
Advisor:Prof. Dr. Philipp Stroebel
Referee:Prof. Dr. Annalen Bleckmann
Referee:Prof. Dr. Ralf Dressel
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EnglishIntroduction: An enhanced understanding of the molecular pathways driving oncogenesis has yielded an increasing number of potential therapeutic targets. MET amplification has been shown to be involved in angiogenesis, cell proliferation, migration, and invasion, as well as cell survival. A pathologic activation of c-MET pathway may occur via met gene amplification, RNA transcription or protein overexpression. This study focused on the relationship between MET-amplification and one of the most prevalent malignancies worldwide- the colorectal carcinoma (CRC). Systemic antibody therapies targeting EGFR and VEGF provide treatment strategies for patients with advanced disease. Development of resistance to targeted therapy is common and c-met alterations are often found in patients with EGFR Inhibitor resistance. The aim of our study was to evaluate the prevalence and prognostic significance of MET protein overexpression, DNA and RNA alteration. Methods: 72 samples were obtained from 62 patients that underwent partial hepatectomies for stage 4 CRC between 2011-2014 at the University Hospital of Goettingen, Goettingen, Germany. C-Met status was examined with fluorescence in situ hybridization (FISH), RNA in situ hybridization (RNA-scope) and immunohistochemistry (IHC). Tissue Mircoarrays (TMA) and a double Z target probe were utilized for RNA-Scope. FISH analysis was carried out with the ZytoLight ® SPEC MET/CEN 7 Dual Color Probe. Results: 40 men and 22 women were included in this study. The mean age was 63 years. We propose a scoring system for IHC considering both membranous and cellular staining pattern. RNA-Scope was evaluated on fluorescent spot count per 100 randomly selected cells. FISH scores were calculated based on centromere to MET-gene ratio. No statistically significant association was found between protein expression, DNA and RNA alteration. Amplification at gene level was much less frequent at 3% than protein overexpression at 29% of cases and RNA amplification at 33%. Gene amplification and mRNA expression does not reliably correlate with protein overexpression, but isolated cases show significant alteration of DNA, RNA and protein expression. Conclusion: Gene alteration is an uncommon cause of enhanced downstream signaling of the c-met kinases pathway in oligometastasized colorectal cancer. The protein expression does not necessarily correlate with gene or RNA amplification and the clinicopathological impact of each mandates further investigation.
Keywords: c-Met, Colorectal cancer