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Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value

BACKGROUND: Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehe...

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Autores principales: Marisa, Laetitia, de Reyniès, Aurélien, Duval, Alex, Selves, Janick, Gaub, Marie Pierre, Vescovo, Laure, Etienne-Grimaldi, Marie-Christine, Schiappa, Renaud, Guenot, Dominique, Ayadi, Mira, Kirzin, Sylvain, Chazal, Maurice, Fléjou, Jean-François, Benchimol, Daniel, Berger, Anne, Lagarde, Arnaud, Pencreach, Erwan, Piard, Françoise, Elias, Dominique, Parc, Yann, Olschwang, Sylviane, Milano, Gérard, Laurent-Puig, Pierre, Boige, Valérie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660251/
https://www.ncbi.nlm.nih.gov/pubmed/23700391
http://dx.doi.org/10.1371/journal.pmed.1001453
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author Marisa, Laetitia
de Reyniès, Aurélien
Duval, Alex
Selves, Janick
Gaub, Marie Pierre
Vescovo, Laure
Etienne-Grimaldi, Marie-Christine
Schiappa, Renaud
Guenot, Dominique
Ayadi, Mira
Kirzin, Sylvain
Chazal, Maurice
Fléjou, Jean-François
Benchimol, Daniel
Berger, Anne
Lagarde, Arnaud
Pencreach, Erwan
Piard, Françoise
Elias, Dominique
Parc, Yann
Olschwang, Sylviane
Milano, Gérard
Laurent-Puig, Pierre
Boige, Valérie
author_facet Marisa, Laetitia
de Reyniès, Aurélien
Duval, Alex
Selves, Janick
Gaub, Marie Pierre
Vescovo, Laure
Etienne-Grimaldi, Marie-Christine
Schiappa, Renaud
Guenot, Dominique
Ayadi, Mira
Kirzin, Sylvain
Chazal, Maurice
Fléjou, Jean-François
Benchimol, Daniel
Berger, Anne
Lagarde, Arnaud
Pencreach, Erwan
Piard, Françoise
Elias, Dominique
Parc, Yann
Olschwang, Sylviane
Milano, Gérard
Laurent-Puig, Pierre
Boige, Valérie
author_sort Marisa, Laetitia
collection PubMed
description BACKGROUND: Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses. METHODS AND FINDINGS: Fresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype–like, normal-like, serrated CC phenotype–like), and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II–III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival, even after adjusting for age, sex, stage, and the emerging prognostic classifier Oncotype DX Colon Cancer Assay recurrence score (hazard ratio 1.5, 95% CI 1.1–2.1, p = 0.0097). However, a limitation of this study is that information on tumor grade and number of nodes examined was not available. CONCLUSIONS: We describe the first, to our knowledge, robust transcriptome-based classification of CC that improves the current disease stratification based on clinicopathological variables and common DNA markers. The biological relevance of these subtypes is illustrated by significant differences in prognosis. This analysis provides possibilities for improving prognostic models and therapeutic strategies. In conclusion, we report a new classification of CC into six molecular subtypes that arise through distinct biological pathways. Please see later in the article for the Editors' Summary
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spelling pubmed-36602512013-05-22 Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value Marisa, Laetitia de Reyniès, Aurélien Duval, Alex Selves, Janick Gaub, Marie Pierre Vescovo, Laure Etienne-Grimaldi, Marie-Christine Schiappa, Renaud Guenot, Dominique Ayadi, Mira Kirzin, Sylvain Chazal, Maurice Fléjou, Jean-François Benchimol, Daniel Berger, Anne Lagarde, Arnaud Pencreach, Erwan Piard, Françoise Elias, Dominique Parc, Yann Olschwang, Sylviane Milano, Gérard Laurent-Puig, Pierre Boige, Valérie PLoS Med Research Article BACKGROUND: Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses. METHODS AND FINDINGS: Fresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype–like, normal-like, serrated CC phenotype–like), and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II–III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival, even after adjusting for age, sex, stage, and the emerging prognostic classifier Oncotype DX Colon Cancer Assay recurrence score (hazard ratio 1.5, 95% CI 1.1–2.1, p = 0.0097). However, a limitation of this study is that information on tumor grade and number of nodes examined was not available. CONCLUSIONS: We describe the first, to our knowledge, robust transcriptome-based classification of CC that improves the current disease stratification based on clinicopathological variables and common DNA markers. The biological relevance of these subtypes is illustrated by significant differences in prognosis. This analysis provides possibilities for improving prognostic models and therapeutic strategies. In conclusion, we report a new classification of CC into six molecular subtypes that arise through distinct biological pathways. Please see later in the article for the Editors' Summary Public Library of Science 2013-05-21 /pmc/articles/PMC3660251/ /pubmed/23700391 http://dx.doi.org/10.1371/journal.pmed.1001453 Text en © 2013 Marisa et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Marisa, Laetitia
de Reyniès, Aurélien
Duval, Alex
Selves, Janick
Gaub, Marie Pierre
Vescovo, Laure
Etienne-Grimaldi, Marie-Christine
Schiappa, Renaud
Guenot, Dominique
Ayadi, Mira
Kirzin, Sylvain
Chazal, Maurice
Fléjou, Jean-François
Benchimol, Daniel
Berger, Anne
Lagarde, Arnaud
Pencreach, Erwan
Piard, Françoise
Elias, Dominique
Parc, Yann
Olschwang, Sylviane
Milano, Gérard
Laurent-Puig, Pierre
Boige, Valérie
Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value
title Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value
title_full Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value
title_fullStr Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value
title_full_unstemmed Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value
title_short Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value
title_sort gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3660251/
https://www.ncbi.nlm.nih.gov/pubmed/23700391
http://dx.doi.org/10.1371/journal.pmed.1001453
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