Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer
Identifieur interne : 000671 ( Main/Exploration ); précédent : 000670; suivant : 000672Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer
Auteurs : Eva Budinska [Suisse, République tchèque] ; Vlad Popovici [Suisse, République tchèque] ; Sabine Tejpar [Belgique] ; Giovanni D'Ario [Suisse] ; Nicolas Lapique [Suisse] ; Katarzyna Otylia Sikora [Suisse] ; Antonio Fabio Di Narzo [Suisse] ; Pu Yan [Suisse] ; John Graeme Hodgson [États-Unis] ; Scott Weinrich [États-Unis] ; Fred Bosman [États-Unis] ; Arnaud Roth [Suisse] ; Mauro Delorenzi [Suisse]Source :
- The Journal of Pathology [ 0022-3417 ] ; 2013-09.
Abstract
The recognition that colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behaviour and response to therapy translates into an urgent need for robust molecular disease subclassifiers that can explain this heterogeneity beyond current parameters (MSI, KRAS, BRAF). Attempts to fill this gap are emerging. The Cancer Genome Atlas (TGCA) reported two main CRC groups, based on the incidence and spectrum of mutated genes, and another paper reported an EMT expression signature defined subgroup. We performed a prior free analysis of CRC heterogeneity on 1113 CRC gene expression profiles and confronted our findings to established molecular determinants and clinical, histopathological and survival data. Unsupervised clustering based on gene modules allowed us to distinguish at least five different gene expression CRC subtypes, which we call surface crypt‐like, lower crypt‐like, CIMP‐H‐like, mesenchymal and mixed. A gene set enrichment analysis combined with literature search of gene module members identified distinct biological motifs in different subtypes. The subtypes, which were not derived based on outcome, nonetheless showed differences in prognosis. Known gene copy number variations and mutations in key cancer‐associated genes differed between subtypes, but the subtypes provided molecular information beyond that contained in these variables. Morphological features significantly differed between subtypes. The objective existence of the subtypes and their clinical and molecular characteristics were validated in an independent set of 720 CRC expression profiles. Our subtypes provide a novel perspective on the heterogeneity of CRC. The proposed subtypes should be further explored retrospectively on existing clinical trial datasets and, when sufficiently robust, be prospectively assessed for clinical relevance in terms of prognosis and treatment response predictive capacity. Original microarray data were uploaded to the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/) under Accession Nos E‐MTAB‐990 and E‐MTAB‐1026. © 2013 Swiss Institute of Bioinformatics. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Url:
DOI: 10.1002/path.4212
Affiliations:
- Belgique, République tchèque, Suisse, États-Unis
- Canton de Berne, Canton de Vaud, Moravie
- Berne, Brno, Lausanne
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level="j" type="abbrev">J. Pathol.</title><idno type="ISSN">0022-3417</idno><idno type="eISSN">1096-9896</idno><imprint><publisher>John Wiley & Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2013-09">2013-09</date><biblScope unit="volume">231</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="63">63</biblScope><biblScope unit="page" to="76">76</biblScope></imprint><idno type="ISSN">0022-3417</idno></series><idno type="istex">3B757F5D40AE2F4F661055EAC851E929126248E5</idno><idno type="DOI">10.1002/path.4212</idno><idno type="ArticleID">PATH4212</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-3417</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">The recognition that colorectal cancer (CRC) is a heterogeneous disease in terms of clinical behaviour and response to therapy translates into an urgent need for robust molecular disease subclassifiers that can explain this heterogeneity beyond current parameters (MSI, KRAS, BRAF). Attempts to fill this gap are emerging. The Cancer Genome Atlas (TGCA) reported two main CRC groups, based on the incidence and spectrum of mutated genes, and another paper reported an EMT expression signature defined subgroup. We performed a prior free analysis of CRC heterogeneity on 1113 CRC gene expression profiles and confronted our findings to established molecular determinants and clinical, histopathological and survival data. Unsupervised clustering based on gene modules allowed us to distinguish at least five different gene expression CRC subtypes, which we call surface crypt‐like, lower crypt‐like, CIMP‐H‐like, mesenchymal and mixed. A gene set enrichment analysis combined with literature search of gene module members identified distinct biological motifs in different subtypes. The subtypes, which were not derived based on outcome, nonetheless showed differences in prognosis. Known gene copy number variations and mutations in key cancer‐associated genes differed between subtypes, but the subtypes provided molecular information beyond that contained in these variables. Morphological features significantly differed between subtypes. The objective existence of the subtypes and their clinical and molecular characteristics were validated in an independent set of 720 CRC expression profiles. Our subtypes provide a novel perspective on the heterogeneity of CRC. The proposed subtypes should be further explored retrospectively on existing clinical trial datasets and, when sufficiently robust, be prospectively assessed for clinical relevance in terms of prognosis and treatment response predictive capacity. Original microarray data were uploaded to the ArrayExpress database (http://www.ebi.ac.uk/arrayexpress/) under Accession Nos E‐MTAB‐990 and E‐MTAB‐1026. © 2013 Swiss Institute of Bioinformatics. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>République tchèque</li><li>Suisse</li><li>États-Unis</li></country><region><li>Canton de Berne</li><li>Canton de Vaud</li><li>Moravie</li></region><settlement><li>Berne</li><li>Brno</li><li>Lausanne</li></settlement></list><tree><country name="Suisse"><region name="Canton de Vaud"><name sortKey="Budinska, Eva" sort="Budinska, Eva" uniqKey="Budinska E" first="Eva" last="Budinska">Eva Budinska</name></region><name sortKey="D Ario, Giovanni" sort="D Ario, Giovanni" uniqKey="D Ario G" first="Giovanni" last="D'Ario">Giovanni D'Ario</name><name sortKey="Delorenzi, Mauro" sort="Delorenzi, Mauro" uniqKey="Delorenzi M" first="Mauro" last="Delorenzi">Mauro Delorenzi</name><name sortKey="Delorenzi, Mauro" sort="Delorenzi, Mauro" uniqKey="Delorenzi M" first="Mauro" last="Delorenzi">Mauro Delorenzi</name><name sortKey="Di Narzo, Antonio Fabio" sort="Di Narzo, Antonio Fabio" uniqKey="Di Narzo A" first="Antonio Fabio" last="Di Narzo">Antonio Fabio Di Narzo</name><name sortKey="Lapique, Nicolas" sort="Lapique, Nicolas" uniqKey="Lapique N" first="Nicolas" last="Lapique">Nicolas Lapique</name><name sortKey="Popovici, Vlad" sort="Popovici, Vlad" uniqKey="Popovici V" first="Vlad" last="Popovici">Vlad Popovici</name><name sortKey="Roth, Arnaud" sort="Roth, Arnaud" uniqKey="Roth A" first="Arnaud" last="Roth">Arnaud Roth</name><name sortKey="Roth, Arnaud" sort="Roth, Arnaud" uniqKey="Roth A" first="Arnaud" last="Roth">Arnaud Roth</name><name sortKey="Sikora, Katarzyna Otylia" sort="Sikora, Katarzyna Otylia" uniqKey="Sikora K" first="Katarzyna Otylia" last="Sikora">Katarzyna Otylia Sikora</name><name sortKey="Yan, Pu" sort="Yan, Pu" uniqKey="Yan P" first="Pu" last="Yan">Pu Yan</name></country><country name="République tchèque"><region name="Moravie"><name sortKey="Budinska, Eva" sort="Budinska, Eva" uniqKey="Budinska E" first="Eva" last="Budinska">Eva Budinska</name></region><name sortKey="Popovici, Vlad" sort="Popovici, Vlad" uniqKey="Popovici V" first="Vlad" last="Popovici">Vlad Popovici</name></country><country name="Belgique"><noRegion><name sortKey="Tejpar, Sabine" sort="Tejpar, Sabine" uniqKey="Tejpar S" first="Sabine" last="Tejpar">Sabine Tejpar</name></noRegion></country><country name="États-Unis"><noRegion><name sortKey="Hodgson, John Graeme" sort="Hodgson, John Graeme" uniqKey="Hodgson J" first="John Graeme" last="Hodgson">John Graeme Hodgson</name></noRegion><name sortKey="Bosman, Fred" sort="Bosman, Fred" uniqKey="Bosman F" first="Fred" last="Bosman">Fred Bosman</name><name sortKey="Weinrich, Scott" sort="Weinrich, Scott" uniqKey="Weinrich S" first="Scott" last="Weinrich">Scott Weinrich</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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