Orthogonal MET analysis in a population-representative stage II-III colon cancer cohort: prognostic and potential therapeutic implications.
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Embargo End Date
ICR Authors
Authors
Craig, SG
Mende, S
Humphries, MP
Bingham, V
Viratham Pulsawatdi, A
Loughrey, MB
Coleman, HG
McQuaid, S
Wilson, RH
Van Schaeybroeck, S
James, JA
Salto-Tellez, M
Mende, S
Humphries, MP
Bingham, V
Viratham Pulsawatdi, A
Loughrey, MB
Coleman, HG
McQuaid, S
Wilson, RH
Van Schaeybroeck, S
James, JA
Salto-Tellez, M
Document Type
Journal Article
Date
2021-12-01
Date Accepted
2021-08-23
Abstract
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 MET-targeted agents. To this aim, orthogonal expression analysis of MET was conducted in a population-representative cohort of stage II/III CC patients (n = 240) 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 dual-colour dual-hapten brightfield in situ hybridisation (DDISH). Expression of transcribed MET and c-MET protein within the cohort was assessed using digital image analysis on MET RNA in situ hybridisation (ISH) and c-MET 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 RNA-ISH/low c-MET IHC protein subgroup was found to be associated with poor 5-year cancer-specific outcomes compared to patients with concordant MET RNA-ISH and c-MET IHC protein expression (HR 2.12 [95%CI: 1.27-3.68]). The MET RNA-ISH/c-MET IHC protein biomarker paradigm identified in this study demonstrates that subtyping of MET expression may be required to identify MET-addicted malignancies in CC patients who will truly benefit from MET inhibition.
Citation
Molecular oncology, 2021, 15 (12), pp. 3317 - 3328
Source Title
Publisher
WILEY
ISSN
1574-7891
eISSN
1878-0261
1878-0261
1878-0261
Collections
Research Team
Integrated Pathology