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 de...

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Autores principales:	Stephanie G. Craig, Svenja Mende, Matthew P. Humphries, Victoria Bingham, Amélie Viratham Pulsawatdi, Maurice B. Loughrey, Helen G. Coleman, Stephen McQuaid, Richard H. Wilson, Sandra Van Schaeybroeck, Jacqueline A. James, Manuel Salto‐Tellez
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	c‐MET IHC protein colon cancer MET amplification MET R970C mutation MET RNA‐ISH MET T992I mutation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/0b8be54a07784f57bd958f3c8b5f5b03
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spelling	oai:doaj.org-article:0b8be54a07784f57bd958f3c8b5f5b032021-12-02T10:31:06ZOrthogonal MET analysis in a population‐representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications1878-02611574-789110.1002/1878-0261.13089https://doaj.org/article/0b8be54a07784f57bd958f3c8b5f5b032021-12-01T00:00:00Zhttps://doi.org/10.1002/1878-0261.13089https://doaj.org/toc/1574-7891https://doaj.org/toc/1878-0261Clinical 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.Stephanie G. CraigSvenja MendeMatthew P. HumphriesVictoria BinghamAmélie Viratham PulsawatdiMaurice B. LoughreyHelen G. ColemanStephen McQuaidRichard H. WilsonSandra Van SchaeybroeckJacqueline A. JamesManuel Salto‐TellezWileyarticlec‐MET IHC proteincolon cancerMET amplificationMET R970C mutationMET RNA‐ISHMET T992I mutationNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Oncology, Vol 15, Iss 12, Pp 3317-3328 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	c‐MET IHC protein colon cancer MET amplification MET R970C mutation MET RNA‐ISH MET T992I mutation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	c‐MET IHC protein colon cancer MET amplification MET R970C mutation MET RNA‐ISH MET T992I mutation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Stephanie G. Craig Svenja Mende Matthew P. Humphries Victoria Bingham Amélie Viratham Pulsawatdi Maurice B. Loughrey Helen G. Coleman Stephen McQuaid Richard H. Wilson Sandra Van Schaeybroeck Jacqueline A. James Manuel Salto‐Tellez Orthogonal MET analysis in a population‐representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications
description	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.
format	article
author	Stephanie G. Craig Svenja Mende Matthew P. Humphries Victoria Bingham Amélie Viratham Pulsawatdi Maurice B. Loughrey Helen G. Coleman Stephen McQuaid Richard H. Wilson Sandra Van Schaeybroeck Jacqueline A. James Manuel Salto‐Tellez
author_facet	Stephanie G. Craig Svenja Mende Matthew P. Humphries Victoria Bingham Amélie Viratham Pulsawatdi Maurice B. Loughrey Helen G. Coleman Stephen McQuaid Richard H. Wilson Sandra Van Schaeybroeck Jacqueline A. James Manuel Salto‐Tellez
author_sort	Stephanie G. Craig
title	Orthogonal MET analysis in a population‐representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications
title_short	Orthogonal MET analysis in a population‐representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications
title_full	Orthogonal MET analysis in a population‐representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications
title_fullStr	Orthogonal MET analysis in a population‐representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications
title_full_unstemmed	Orthogonal MET analysis in a population‐representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications
title_sort	orthogonal met analysis in a population‐representative stage ii–iii colon cancer cohort: prognostic and potential therapeutic implications
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/0b8be54a07784f57bd958f3c8b5f5b03
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Orthogonal MET analysis in a population‐representative stage II–III colon cancer cohort: prognostic and potential therapeutic implications

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