Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value.
<h4>Background</h4>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 e...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2013
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/05db3f0cfd2241469580f61ac65f8620 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:05db3f0cfd2241469580f61ac65f8620 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:05db3f0cfd2241469580f61ac65f86202021-11-18T05:42:36ZGene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value.1549-12771549-167610.1371/journal.pmed.1001453https://doaj.org/article/05db3f0cfd2241469580f61ac65f86202013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23700391/pdf/?tool=EBIhttps://doaj.org/toc/1549-1277https://doaj.org/toc/1549-1676<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.Laetitia MarisaAurélien de ReynièsAlex DuvalJanick SelvesMarie Pierre GaubLaure VescovoMarie-Christine Etienne-GrimaldiRenaud SchiappaDominique GuenotMira AyadiSylvain KirzinMaurice ChazalJean-François FléjouDaniel BenchimolAnne BergerArnaud LagardeErwan PencreachFrançoise PiardDominique EliasYann ParcSylviane OlschwangGérard MilanoPierre Laurent-PuigValérie BoigePublic Library of Science (PLoS)articleMedicineRENPLoS Medicine, Vol 10, Iss 5, p e1001453 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R |
| spellingShingle |
Medicine R Laetitia Marisa Aurélien de Reyniès Alex Duval Janick Selves Marie Pierre Gaub Laure Vescovo Marie-Christine Etienne-Grimaldi Renaud Schiappa Dominique Guenot Mira Ayadi Sylvain Kirzin Maurice Chazal Jean-François Fléjou Daniel Benchimol Anne Berger Arnaud Lagarde Erwan Pencreach Françoise Piard Dominique Elias Yann Parc Sylviane Olschwang Gérard Milano Pierre Laurent-Puig Valérie Boige Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. |
| description |
<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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. |
| format |
article |
| author |
Laetitia Marisa Aurélien de Reyniès Alex Duval Janick Selves Marie Pierre Gaub Laure Vescovo Marie-Christine Etienne-Grimaldi Renaud Schiappa Dominique Guenot Mira Ayadi Sylvain Kirzin Maurice Chazal Jean-François Fléjou Daniel Benchimol Anne Berger Arnaud Lagarde Erwan Pencreach Françoise Piard Dominique Elias Yann Parc Sylviane Olschwang Gérard Milano Pierre Laurent-Puig Valérie Boige |
| author_facet |
Laetitia Marisa Aurélien de Reyniès Alex Duval Janick Selves Marie Pierre Gaub Laure Vescovo Marie-Christine Etienne-Grimaldi Renaud Schiappa Dominique Guenot Mira Ayadi Sylvain Kirzin Maurice Chazal Jean-François Fléjou Daniel Benchimol Anne Berger Arnaud Lagarde Erwan Pencreach Françoise Piard Dominique Elias Yann Parc Sylviane Olschwang Gérard Milano Pierre Laurent-Puig Valérie Boige |
| author_sort |
Laetitia Marisa |
| title |
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_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_sort |
gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/05db3f0cfd2241469580f61ac65f8620 |
| work_keys_str_mv |
AT laetitiamarisa geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT aureliendereynies geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT alexduval geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT janickselves geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT mariepierregaub geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT laurevescovo geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT mariechristineetiennegrimaldi geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT renaudschiappa geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT dominiqueguenot geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT miraayadi geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT sylvainkirzin geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT mauricechazal geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT jeanfrancoisflejou geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT danielbenchimol geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT anneberger geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT arnaudlagarde geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT erwanpencreach geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT francoisepiard geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT dominiqueelias geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT yannparc geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT sylvianeolschwang geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT gerardmilano geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT pierrelaurentpuig geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue AT valerieboige geneexpressionclassificationofcoloncancerintomolecularsubtypescharacterizationvalidationandprognosticvalue |
| _version_ |
1718424769479573504 |