A combined oncogenic pathway signature of BRAF, KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction
Identifieur interne : 000429 ( Main/Exploration ); précédent : 000428; suivant : 000430A combined oncogenic pathway signature of BRAF, KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction
Auteurs : Sun Tian [Pays-Bas] ; Iris Simon [Pays-Bas] ; Victor Moreno [Espagne] ; Paul Roepman [Pays-Bas] ; Josep Tabernero [Espagne] ; Mireille Snel [Pays-Bas] ; Laura Van'T Veer [Pays-Bas] ; Ramon Salazar [Espagne] ; Rene Bernards [Pays-Bas] ; Gabriel Capella [Espagne, Niger]Source :
- Gut [ 0017-5749 ] ; 2013-04.
Abstract
Objective To develop gene expression profiles that characterise KRAS-, BRAF- or PIK3CA-activated- tumours, and to explore whether these profiles might be helpful in predicting the response to the epidermal growth factor receptor (EGFR) pathway inhibitors better than mutation status alone. Design Fresh frozen tumour samples from 381 colorectal cancer (CRC) patients were collected and mutations in KRAS, BRAF and PIK3CA were assessed. Using microarray data, three individual oncogenic and a combined model were developed and validated in an independent set of 80 CRC patients, and in a dataset from metastatic CRC patients treated with cetuximab. Results 175 tumours (45.9%) harboured oncogenic mutations in KRAS (30.2%), BRAF (11.0%) and PIK3CA (11.5%). Activating mutation signatures for KRAS (75 genes), for BRAF (58 genes,) and for PIK3CA (49 genes) were developed. The development of a combined oncogenic pathway signature-classified tumours as ‘activated oncogenic’, or as ‘wildtype-like’ with a sensitivity of 90.3% and a specificity of 61.7%. The identified signature revealed other mechanisms that can activate ERK/MAPK pathway in KRAS, BRAF and PIK3CA wildtype patients. The combined signature is associated with response to cetuximab treatment in patients with metastatic CRC (HR 2.51, p<0.0009). Conclusion A combined oncogenic pathway signature allows the identification of patients with an active EGFR-signalling pathway that could benefit from downstream pathway inhibition.
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DOI: 10.1136/gutjnl-2012-302423
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type="province">Hollande-Septentrionale</region></placeName></affiliation></author><author><name sortKey="Salazar, Ramon" sort="Salazar, Ramon" uniqKey="Salazar R" first="Ramon" last="Salazar">Ramon Salazar</name><affiliation wicri:level="1"><country xml:lang="fr">Espagne</country><wicri:regionArea>IDIBELL, Institut Català d'Oncologia, L'Hospitalet de Llobregat</wicri:regionArea><wicri:noRegion>L'Hospitalet de Llobregat</wicri:noRegion></affiliation></author><author><name sortKey="Bernards, Rene" sort="Bernards, Rene" uniqKey="Bernards R" first="Rene" last="Bernards">Rene Bernards</name><affiliation wicri:level="3"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Research and Development, Agendia BV, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam</wicri:regionArea><placeName><settlement type="city">Amsterdam</settlement><region nuts="2" type="province">Hollande-Septentrionale</region></placeName></affiliation></author><author><name sortKey="Capella, Gabriel" sort="Capella, Gabriel" uniqKey="Capella G" first="Gabriel" last="Capella">Gabriel Capella</name><affiliation wicri:level="1"><country xml:lang="fr">Espagne</country><wicri:regionArea>IDIBELL, Institut Català d'Oncologia, L'Hospitalet de Llobregat</wicri:regionArea><wicri:noRegion>L'Hospitalet de Llobregat</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Niger</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Gut</title><title level="j" type="abbrev">Gut</title><idno type="ISSN">0017-5749</idno><idno type="eISSN">1468-3288</idno><imprint><publisher>BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><date type="published" when="2013-04">2013-04</date><biblScope unit="volume">62</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="540">540</biblScope></imprint><idno type="ISSN">0017-5749</idno></series><idno type="istex">22BE012584E38ABE493C6FB965128209A9ED4A41</idno><idno type="DOI">10.1136/gutjnl-2012-302423</idno><idno type="href">gutjnl-62-540.pdf</idno><idno type="ArticleID">gutjnl-2012-302423</idno><idno type="PMID">22798500</idno><idno type="local">gutjnl;62/4/540</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0017-5749</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Objective To develop gene expression profiles that characterise KRAS-, BRAF- or PIK3CA-activated- tumours, and to explore whether these profiles might be helpful in predicting the response to the epidermal growth factor receptor (EGFR) pathway inhibitors better than mutation status alone. Design Fresh frozen tumour samples from 381 colorectal cancer (CRC) patients were collected and mutations in KRAS, BRAF and PIK3CA were assessed. Using microarray data, three individual oncogenic and a combined model were developed and validated in an independent set of 80 CRC patients, and in a dataset from metastatic CRC patients treated with cetuximab. Results 175 tumours (45.9%) harboured oncogenic mutations in KRAS (30.2%), BRAF (11.0%) and PIK3CA (11.5%). Activating mutation signatures for KRAS (75 genes), for BRAF (58 genes,) and for PIK3CA (49 genes) were developed. The development of a combined oncogenic pathway signature-classified tumours as ‘activated oncogenic’, or as ‘wildtype-like’ with a sensitivity of 90.3% and a specificity of 61.7%. The identified signature revealed other mechanisms that can activate ERK/MAPK pathway in KRAS, BRAF and PIK3CA wildtype patients. The combined signature is associated with response to cetuximab treatment in patients with metastatic CRC (HR 2.51, p<0.0009). Conclusion A combined oncogenic pathway signature allows the identification of patients with an active EGFR-signalling pathway that could benefit from downstream pathway inhibition.</div></front></TEI><affiliations><list><country><li>Espagne</li><li>Niger</li><li>Pays-Bas</li></country><region><li>Catalogne</li><li>Hollande-Septentrionale</li></region><settlement><li>Amsterdam</li><li>Barcelone</li></settlement></list><tree><country name="Pays-Bas"><region name="Hollande-Septentrionale"><name sortKey="Tian, Sun" sort="Tian, Sun" uniqKey="Tian S" first="Sun" last="Tian">Sun Tian</name></region><name sortKey="Bernards, Rene" sort="Bernards, Rene" uniqKey="Bernards R" first="Rene" last="Bernards">Rene Bernards</name><name sortKey="Bernards, Rene" sort="Bernards, Rene" uniqKey="Bernards R" first="Rene" last="Bernards">Rene Bernards</name><name sortKey="Roepman, Paul" sort="Roepman, Paul" uniqKey="Roepman P" first="Paul" last="Roepman">Paul Roepman</name><name sortKey="Simon, Iris" sort="Simon, Iris" uniqKey="Simon I" first="Iris" last="Simon">Iris Simon</name><name sortKey="Snel, Mireille" sort="Snel, Mireille" uniqKey="Snel M" first="Mireille" last="Snel">Mireille Snel</name><name sortKey="Van T Veer, Laura" sort="Van T Veer, Laura" uniqKey="Van T Veer L" first="Laura" last="Van'T Veer">Laura Van'T Veer</name></country><country name="Espagne"><noRegion><name sortKey="Moreno, Victor" sort="Moreno, Victor" uniqKey="Moreno V" first="Victor" last="Moreno">Victor Moreno</name></noRegion><name sortKey="Capella, Gabriel" sort="Capella, Gabriel" uniqKey="Capella G" first="Gabriel" last="Capella">Gabriel Capella</name><name sortKey="Moreno, Victor" sort="Moreno, Victor" uniqKey="Moreno V" first="Victor" last="Moreno">Victor Moreno</name><name sortKey="Salazar, Ramon" sort="Salazar, Ramon" uniqKey="Salazar R" first="Ramon" last="Salazar">Ramon Salazar</name><name sortKey="Tabernero, Josep" sort="Tabernero, Josep" uniqKey="Tabernero J" first="Josep" last="Tabernero">Josep Tabernero</name></country><country name="Niger"><noRegion><name sortKey="Capella, Gabriel" sort="Capella, Gabriel" uniqKey="Capella G" first="Gabriel" last="Capella">Gabriel Capella</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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