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    Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome.

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    Authors
    Scholl, Suzy
    Popovic, Marina
    de la Rochefordiere, Anne
    Girard, Elodie
    Dureau, Sylvain
    Mandic, Aljosa
    Koprivsek, Katarina
    Samet, Nina
    Craina, Marius
    Margan, Madalin
    Samuels, Sanne
    Zijlmans, Henry
    Kenter, Gemma
    Hillemanns, Peter
    Dema, Sorin
    Dema, Alis
    Malenkovic, Goran
    Djuran, Branislav
    Floquet, Anne
    Garbay, Delphine
    Guyon, Frédéric
    Colombo, Pierre Emmanuel
    Fabbro, Michel
    Kerr, Christine
    Ngo, Charlotte
    Lecuru, Fabrice
    Campo, Eleonor Rivin Del
    Coutant, Charles
    Marchal, Frédéric
    Mesgouez-Nebout, Nathalie
    Fourchotte, Virginie
    Feron, Jean Guillaume
    Morice, Philippe
    Deutsch, Eric
    Wimberger, Pauline
    Classe, Jean-Marc
    Gleeson, Noreen
    von der Leyen, Heiko
    Minsat, Mathieu
    Dubot, Coraline
    Gestraud, Pierre
    Kereszt, Attila
    Nagy, Istvan
    Balint, Balazs
    Berns, Els
    Jordanova, Ekaterina
    Saint-Jorre, Nicolas de
    Savignoni, Alexia
    Servant, Nicolas
    Hupe, Philippe
    de Koning, Leanne
    Fumoleau, Pierre
    Rouzier, Roman
    Kamal, Maud
    Show allShow less
    Issue Date
    2019-04-02
    Keywords
    Bioraids study
    Cervical cancers
    Epigenetics pathways
    PI3KCA
    Patient stratification
    Prospective database
    Reverse phase protein array
    Whole exome sequencing
    
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    Journal
    EBioMedicine
    URI
    http://hdl.handle.net/10147/627176
    DOI
    10.1016/j.ebiom.2019.03.069
    PubMed ID
    30952619
    Abstract
    Background: 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.
    Item Type
    Article
    Language
    en
    EISSN
    2352-3964
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.ebiom.2019.03.069
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