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External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS

BACKGROUND: Competing molecular classification systems have been proposed to complement the TNM staging system for a better prediction of survival in colorectal cancer (CRC). However, validation studies are so far lacking. The aim of this study was to validate and extend previously published molecul...

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Autores principales: Alwers, Elizabeth, Bläker, Hendrik, Walter, Viola, Jansen, Lina, Kloor, Matthias, Arnold, Alexander, Sieber-Frank, Julia, Herpel, Esther, Tagscherer, Katrin E., Roth, Wilfried, Chang-Claude, Jenny, Brenner, Hermann, Hoffmeister, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624952/
https://www.ncbi.nlm.nih.gov/pubmed/31296182
http://dx.doi.org/10.1186/s12885-019-5842-7
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author Alwers, Elizabeth
Bläker, Hendrik
Walter, Viola
Jansen, Lina
Kloor, Matthias
Arnold, Alexander
Sieber-Frank, Julia
Herpel, Esther
Tagscherer, Katrin E.
Roth, Wilfried
Chang-Claude, Jenny
Brenner, Hermann
Hoffmeister, Michael
author_facet Alwers, Elizabeth
Bläker, Hendrik
Walter, Viola
Jansen, Lina
Kloor, Matthias
Arnold, Alexander
Sieber-Frank, Julia
Herpel, Esther
Tagscherer, Katrin E.
Roth, Wilfried
Chang-Claude, Jenny
Brenner, Hermann
Hoffmeister, Michael
author_sort Alwers, Elizabeth
collection PubMed
description BACKGROUND: Competing molecular classification systems have been proposed to complement the TNM staging system for a better prediction of survival in colorectal cancer (CRC). However, validation studies are so far lacking. The aim of this study was to validate and extend previously published molecular classifications of CRC in a large independent cohort of CRC patients. METHODS: CRC patients were recruited into a population-based cohort study (DACHS). Molecular subtypes were categorized based on three previously published classifications. Cox-proportional hazard models, based on the same set of patients and using the same confounders as reported by the original studies, were used to determine overall, cancer-specific, or relapse-free survival for each subtype. Hazard ratios and confidence intervals, as well as Kaplan-Meier plots were compared to those reported by the original studies. RESULTS: We observed similar patterns of worse survival for the microsatellite stable (MSS)/BRAF-mutated and MSS/KRAS-mutated subtypes in our validation analyses, which were included in two of the validated classifications. Of the two MSI subtypes, one defined by additional presence of CIMP-high and BRAF-mutation and the other by tumors negative for CIMP, BRAF and KRAS-mutations, we could not confirm associations with better prognosis as suggested by one of the classifications. For two of the published classifications, we were able to provide results for additional subgroups not included in the original studies (men, other disease stages, other locations). CONCLUSIONS: External validation of three previously proposed classifications confirmed findings of worse survival for CRC patients with MSS subtypes and BRAF or KRAS mutations. Regarding MSI subtypes, other patient characteristics such as stage of the tumor, may influence the potential survival benefit. Further integration of methylation, genetic, and immunological information is needed to develop and validate a comprehensive classification that will have relevance for use in clinical practice.
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spelling pubmed-66249522019-07-23 External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS Alwers, Elizabeth Bläker, Hendrik Walter, Viola Jansen, Lina Kloor, Matthias Arnold, Alexander Sieber-Frank, Julia Herpel, Esther Tagscherer, Katrin E. Roth, Wilfried Chang-Claude, Jenny Brenner, Hermann Hoffmeister, Michael BMC Cancer Research Article BACKGROUND: Competing molecular classification systems have been proposed to complement the TNM staging system for a better prediction of survival in colorectal cancer (CRC). However, validation studies are so far lacking. The aim of this study was to validate and extend previously published molecular classifications of CRC in a large independent cohort of CRC patients. METHODS: CRC patients were recruited into a population-based cohort study (DACHS). Molecular subtypes were categorized based on three previously published classifications. Cox-proportional hazard models, based on the same set of patients and using the same confounders as reported by the original studies, were used to determine overall, cancer-specific, or relapse-free survival for each subtype. Hazard ratios and confidence intervals, as well as Kaplan-Meier plots were compared to those reported by the original studies. RESULTS: We observed similar patterns of worse survival for the microsatellite stable (MSS)/BRAF-mutated and MSS/KRAS-mutated subtypes in our validation analyses, which were included in two of the validated classifications. Of the two MSI subtypes, one defined by additional presence of CIMP-high and BRAF-mutation and the other by tumors negative for CIMP, BRAF and KRAS-mutations, we could not confirm associations with better prognosis as suggested by one of the classifications. For two of the published classifications, we were able to provide results for additional subgroups not included in the original studies (men, other disease stages, other locations). CONCLUSIONS: External validation of three previously proposed classifications confirmed findings of worse survival for CRC patients with MSS subtypes and BRAF or KRAS mutations. Regarding MSI subtypes, other patient characteristics such as stage of the tumor, may influence the potential survival benefit. Further integration of methylation, genetic, and immunological information is needed to develop and validate a comprehensive classification that will have relevance for use in clinical practice. BioMed Central 2019-07-11 /pmc/articles/PMC6624952/ /pubmed/31296182 http://dx.doi.org/10.1186/s12885-019-5842-7 Text en © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Alwers, Elizabeth
Bläker, Hendrik
Walter, Viola
Jansen, Lina
Kloor, Matthias
Arnold, Alexander
Sieber-Frank, Julia
Herpel, Esther
Tagscherer, Katrin E.
Roth, Wilfried
Chang-Claude, Jenny
Brenner, Hermann
Hoffmeister, Michael
External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS
title External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS
title_full External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS
title_fullStr External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS
title_full_unstemmed External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS
title_short External validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, CIMP, BRAF and KRAS
title_sort external validation of molecular subtype classifications of colorectal cancer based on microsatellite instability, cimp, braf and kras
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624952/
https://www.ncbi.nlm.nih.gov/pubmed/31296182
http://dx.doi.org/10.1186/s12885-019-5842-7
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