CLO22-061: c-MET Alteration in Patients With Metastasized Colorectal Carcinoma – An Evaluation of Methods of Detection, Clinical Impact and Discussion of c-MET as Potential Therapeutic Target

Authors: Amelie Lueders MD1, Annalen Bleckmann Dr Med2, Tim Beißbarth Prof Dr3, and Hans-Ulrich Schildhaus Prof Dr Med4
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  • 1 Ascension Indiana: Ascension St Vincent, Carmel, IN
  • | 2 University Hospital Münster, University of Münster, Münster, Germany
  • | 3 University of Göttingen, Göttingen, Germany
  • | 4 University Hospital Essen, Essen, Germany

INTRODUCTION: 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 and survival, migration, and invasion. A pathologic activation of c-MET pathway may occur via met gene amplification, activating mutations and gene fusions, RNA transcription or protein overexpression. This study focused on the relationship between c-MET-amplification and 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 c-MET protein overexpression, DNA and RNA alteration. Methods: 72 samples were obtained from 62 oligometastatic patients that underwent partial hepatectomies for stage IV CRC. C-Met status was examined with fluorescence in situ hybridization (FISH), RNA in situ hybridization (RNA ISH) and immunohistochemistry (IHC). Tissue Mircoarrays (TMA) and specific anti RNA probes (Bio-Techne) were utilized for semiquantitative analysis of RNA ISH. FISH analysis was carried out with the ZytoLight ® SPEC MET/CEN 7 Dual Color Probe. FISH scores were calculated based on centromere to MET-gene ratio and the average gene signal count per tumor cell. The SP44 antibody clone (Ventana) was used for IHC. 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 membranous and cellular staining pattern. 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 oligometastatic colorectal cancer. Protein expression does not necessarily correlate with gene or RNA amplification and the clinicopathological impact of each mandates further investigation.

Corresponding Author: Amelie Lueders, MD
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