Orthogonal MET analysis in a population-representative stage II-III colon cancer cohort: prognostic and potential therapeutic implications

Stephanie G. Craig; Svenja Mende; Matthew Humphries; Victoria Bingham; Amélie Viratham Pulsawatdi; Maurice B. Loughrey; Helen G Coleman; Stephen McQuaid; Richard Wilson; Sandra Van Schaeybroeck; Jacqueline A James; Manuel Salto-Tellez

doi:10.1002/1878-0261.13089

Orthogonal MET analysis in a population-representative stage II-III colon cancer cohort: prognostic and potential therapeutic implications

Stephanie G. Craig, Svenja Mende, Matthew Humphries, Victoria Bingham, Amélie Viratham Pulsawatdi, Maurice B. Loughrey, Helen G Coleman, Stephen McQuaid, Richard Wilson, Sandra Van Schaeybroeck, Jacqueline A James, Manuel Salto-Tellez^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Journal	Molecular oncology
Early online date	01 Nov 2021
DOIs	https://doi.org/10.1002/1878-0261.13089
Publication status	Early online date - 01 Nov 2021

Bibliographical note

Funding Information:
The samples in the Epi700 cohort were received from the Northern Ireland Biobank, which has received funds from the Health and Social Care Research and Development Division of the Public Health Agency in Northern Ireland, Cancer Research UK and the Friends of the Cancer Centre. We would like to thank and acknowledge Dr Ronan T. Gray for his contribution to the mutational data linked to the Epi700 cohort which was previously generated through a Cancer Research UK (CRUK) Research Bursary (C50104/A17592). We would like to acknowledge MErCuRIC clinical trial which was funded by the European Commission's Framework Programme 7, under contract #602901 which prompted us to address MET expression in a population‐representative colon cohort. The Precision Medicine Centre of Excellence has received funding from Invest Northern Ireland, Cancer Research UK, the Health and Social Care Research and Development Division of the Public Health Agency in Northern Ireland, the Sean Crummey Memorial Fund and the Tom Simms Memorial Fund. This study was supported by a Cancer Research UK Accelerator grant (C11512/A20256) and supported Tom Simms Memorial Fund. The funders had no role in study design, collection, data analysis or interpretation of the data.

Publisher Copyright:
© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies

Keywords

MET R970C mutation
MET RNA‐ISH
MET T992I mutation
MET amplification
Research Article
Research Articles
colon cancer
c‐MET IHC protein

ASJC Scopus subject areas

Molecular Medicine
Genetics
Oncology
Cancer Research

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Orthogonal MET analysis in a population-representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications
Copyright 2021 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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Craig, S. G., Mende, S., Humphries, M., Bingham, V., Viratham Pulsawatdi, A., Loughrey, M. B., Coleman, H. G., McQuaid, S., Wilson, R., Van Schaeybroeck, S., James, J. A., & Salto-Tellez, M. (2021). Orthogonal MET analysis in a population-representative stage II-III colon cancer cohort: prognostic and potential therapeutic implications. Molecular oncology. Advance online publication. https://doi.org/10.1002/1878-0261.13089

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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.",

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note = "Funding Information: The samples in the Epi700 cohort were received from the Northern Ireland Biobank, which has received funds from the Health and Social Care Research and Development Division of the Public Health Agency in Northern Ireland, Cancer Research UK and the Friends of the Cancer Centre. We would like to thank and acknowledge Dr Ronan T. Gray for his contribution to the mutational data linked to the Epi700 cohort which was previously generated through a Cancer Research UK (CRUK) Research Bursary (C50104/A17592). We would like to acknowledge MErCuRIC clinical trial which was funded by the European Commission's Framework Programme 7, under contract #602901 which prompted us to address MET expression in a population‐representative colon cohort. The Precision Medicine Centre of Excellence has received funding from Invest Northern Ireland, Cancer Research UK, the Health and Social Care Research and Development Division of the Public Health Agency in Northern Ireland, the Sean Crummey Memorial Fund and the Tom Simms Memorial Fund. This study was supported by a Cancer Research UK Accelerator grant (C11512/A20256) and supported Tom Simms Memorial Fund. The funders had no role in study design, collection, data analysis or interpretation of the data. Publisher Copyright: {\textcopyright} 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies",

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Craig, SG, Mende, S, Humphries, M, Bingham, V, Viratham Pulsawatdi, A, Loughrey, MB, Coleman, HG, McQuaid, S, Wilson, R, Van Schaeybroeck, S , James, JA & Salto-Tellez, M 2021, 'Orthogonal MET analysis in a population-representative stage II-III colon cancer cohort: prognostic and potential therapeutic implications', Molecular oncology. https://doi.org/10.1002/1878-0261.13089

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AU - Craig, Stephanie G.

AU - Mende, Svenja

AU - Humphries, Matthew

AU - Bingham, Victoria

AU - Viratham Pulsawatdi, Amélie

AU - Loughrey, Maurice B.

AU - Coleman, Helen G

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AU - Wilson, Richard

AU - Van Schaeybroeck, Sandra

AU - James, Jacqueline A

AU - Salto-Tellez, Manuel

N1 - Funding Information: The samples in the Epi700 cohort were received from the Northern Ireland Biobank, which has received funds from the Health and Social Care Research and Development Division of the Public Health Agency in Northern Ireland, Cancer Research UK and the Friends of the Cancer Centre. We would like to thank and acknowledge Dr Ronan T. Gray for his contribution to the mutational data linked to the Epi700 cohort which was previously generated through a Cancer Research UK (CRUK) Research Bursary (C50104/A17592). We would like to acknowledge MErCuRIC clinical trial which was funded by the European Commission's Framework Programme 7, under contract #602901 which prompted us to address MET expression in a population‐representative colon cohort. The Precision Medicine Centre of Excellence has received funding from Invest Northern Ireland, Cancer Research UK, the Health and Social Care Research and Development Division of the Public Health Agency in Northern Ireland, the Sean Crummey Memorial Fund and the Tom Simms Memorial Fund. This study was supported by a Cancer Research UK Accelerator grant (C11512/A20256) and supported Tom Simms Memorial Fund. The funders had no role in study design, collection, data analysis or interpretation of the data. Publisher Copyright: © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies

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JF - Molecular oncology

ER -

Orthogonal MET analysis in a population-representative stage II-III colon cancer cohort: prognostic and potential therapeutic implications

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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