1 research outputs found
Orthogonal MET analysis in a population-representative stage II-III colon cancer cohort: prognostic and potential therapeutic implications
Clinical trials for MET inhibitors have demonstrated limited success for their use in colon cancer (CC). However, clinical efficacy may be obscured by a lack of standardisation in MET assessment for patient stratification. In this study, we aimed to determine the molecular context in which MET is deregulated in CC using a series of genomic and proteomic tests to define MET expression and identify patient subgroups that should be considered in future studies with METâtargeted agents. To this aim, orthogonal expression analysis of MET was conducted in a populationârepresentative cohort of stage II/III CC patients (nâ=â240) diagnosed in Northern Ireland from 2004 to 2008. Targeted sequencing was used to determine the relative incidence of MET R970C and MET T992I mutations within the cohort. MET amplification was assessed using dualâcolour dualâhapten brightfield inâsitu hybridisation (DDISH). Expression of transcribed MET and câMET protein within the cohort was assessed using digital image analysis on MET RNA inâsitu hybridisation (ISH) and câMET immunohistochemistry (IHC) stained slides. We found that less than 2% of the stage II/III CC patient population assessed demonstrated a genetic MET aberration. Determination of a high MET RNAâISH/low câMET IHC protein subgroup was found to be associated with poor 5âyear cancerâspecific outcomes compared to patients with concordant MET RNAâISH and câMET IHC protein expression (HR 2.12 [95%CI: 1.27â3.68]). The MET RNAâISH/câMET IHC protein biomarker paradigm identified in this study demonstrates that subtyping of MET expression may be required to identify METâaddicted malignancies in CC patients who will truly benefit from MET inhibition