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dc.contributor.authorScholl, Suzy
dc.contributor.authorPopovic, Marina
dc.contributor.authorde la Rochefordiere, Anne
dc.contributor.authorGirard, Elodie
dc.contributor.authorDureau, Sylvain
dc.contributor.authorMandic, Aljosa
dc.contributor.authorKoprivsek, Katarina
dc.contributor.authorSamet, Nina
dc.contributor.authorCraina, Marius
dc.contributor.authorMargan, Madalin
dc.contributor.authorSamuels, Sanne
dc.contributor.authorZijlmans, Henry
dc.contributor.authorKenter, Gemma
dc.contributor.authorHillemanns, Peter
dc.contributor.authorDema, Sorin
dc.contributor.authorDema, Alis
dc.contributor.authorMalenkovic, Goran
dc.contributor.authorDjuran, Branislav
dc.contributor.authorFloquet, Anne
dc.contributor.authorGarbay, Delphine
dc.contributor.authorGuyon, Frédéric
dc.contributor.authorColombo, Pierre Emmanuel
dc.contributor.authorFabbro, Michel
dc.contributor.authorKerr, Christine
dc.contributor.authorNgo, Charlotte
dc.contributor.authorLecuru, Fabrice
dc.contributor.authorCampo, Eleonor Rivin Del
dc.contributor.authorCoutant, Charles
dc.contributor.authorMarchal, Frédéric
dc.contributor.authorMesgouez-Nebout, Nathalie
dc.contributor.authorFourchotte, Virginie
dc.contributor.authorFeron, Jean Guillaume
dc.contributor.authorMorice, Philippe
dc.contributor.authorDeutsch, Eric
dc.contributor.authorWimberger, Pauline
dc.contributor.authorClasse, Jean-Marc
dc.contributor.authorGleeson, Noreen
dc.contributor.authorvon der Leyen, Heiko
dc.contributor.authorMinsat, Mathieu
dc.contributor.authorDubot, Coraline
dc.contributor.authorGestraud, Pierre
dc.contributor.authorKereszt, Attila
dc.contributor.authorNagy, Istvan
dc.contributor.authorBalint, Balazs
dc.contributor.authorBerns, Els
dc.contributor.authorJordanova, Ekaterina
dc.contributor.authorSaint-Jorre, Nicolas de
dc.contributor.authorSavignoni, Alexia
dc.contributor.authorServant, Nicolas
dc.contributor.authorHupe, Philippe
dc.contributor.authorde Koning, Leanne
dc.contributor.authorFumoleau, Pierre
dc.contributor.authorRouzier, Roman
dc.contributor.authorKamal, Maud
dc.date.accessioned2020-02-11T12:00:13Z
dc.date.available2020-02-11T12:00:13Z
dc.date.issued2019-04-02
dc.identifier.pmid30952619
dc.identifier.doi10.1016/j.ebiom.2019.03.069
dc.identifier.urihttp://hdl.handle.net/10147/627176
dc.description.abstractBackground: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810.en_US
dc.language.isoenen_US
dc.rightsCopyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
dc.subjectBioraids studyen_US
dc.subjectCervical cancersen_US
dc.subjectEpigenetics pathwaysen_US
dc.subjectPI3KCAen_US
dc.subjectPatient stratificationen_US
dc.subjectProspective databaseen_US
dc.subjectReverse phase protein arrayen_US
dc.subjectWhole exome sequencingen_US
dc.titleClinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome.en_US
dc.typeArticleen_US
dc.identifier.eissn2352-3964
dc.identifier.journalEBioMedicineen_US
dc.description.provinceLeinsteren_US
dc.description.peer-reviewpeer-reviewen_US
dc.source.journaltitleEBioMedicine
dc.source.volume43
dc.source.beginpage253
dc.source.endpage260
refterms.dateFOA2020-02-11T12:00:13Z
dc.source.countryNetherlands


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