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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Suzy Scholl - , Institut Curie (Autor:in)
  • Marina Popovic - , Oncology Institute of Vojvodina (Autor:in)
  • Anne de la Rochefordiere - , Institut Curie (Autor:in)
  • Elodie Girard - , Institut Curie (Autor:in)
  • Sylvain Dureau - , Institut Curie (Autor:in)
  • Aljosa Mandic - , Oncology Institute of Vojvodina (Autor:in)
  • Katarina Koprivsek - , Oncology Institute of Vojvodina (Autor:in)
  • Nina Samet - , Publica Institutul Oncologic (Autor:in)
  • Marius Craina - , Victor Babes University of Medicine and Pharmacy (Autor:in)
  • Madalin Margan - , Victor Babes University of Medicine and Pharmacy (Autor:in)
  • Sanne Samuels - , Antoni van Leeuwenhoek Hospital (Autor:in)
  • Henry Zijlmans - , Antoni van Leeuwenhoek Hospital (Autor:in)
  • Gemma Kenter - , Antoni van Leeuwenhoek Hospital (Autor:in)
  • Peter Hillemanns - , Medizinische Hochschule Hannover (MHH) (Autor:in)
  • Sorin Dema - , Victor Babes University of Medicine and Pharmacy (Autor:in)
  • Alis Dema - , Victor Babes University of Medicine and Pharmacy (Autor:in)
  • Goran Malenkovic - , Oncology Institute of Vojvodina (Autor:in)
  • Branislav Djuran - , Oncology Institute of Vojvodina (Autor:in)
  • Anne Floquet - , Centre Georges-François Leclerc (Autor:in)
  • Delphine Garbay - , Centre Georges-François Leclerc (Autor:in)
  • Frédéric Guyon - , Centre Georges-François Leclerc (Autor:in)
  • Pierre Emmanuel Colombo - , Centre régional de lutte du cancer Val d'Aurelle (Autor:in)
  • Michel Fabbro - , Centre régional de lutte du cancer Val d'Aurelle (Autor:in)
  • Christine Kerr - , Centre régional de lutte du cancer Val d'Aurelle (Autor:in)
  • Charlotte Ngo - , Hopital Europeen Georges-Pompidou (Autor:in)
  • Fabrice Lecuru - , Hopital Europeen Georges-Pompidou (Autor:in)
  • Eleonor Rivin del Campo - , Hopital Tenon (Autor:in)
  • Charles Coutant - , Centre Georges-François Leclerc (Autor:in)
  • Frédéric Marchal - , Université de Lorraine (Autor:in)
  • Nathalie Mesgouez-Nebout - , Institute de Cancérologie de l'Ouest (Autor:in)
  • Virginie Fourchotte - , Institut Curie (Autor:in)
  • Jean Guillaume Feron - , Institut Curie (Autor:in)
  • Philippe Morice - , Institut Gustave Roussy (Autor:in)
  • Eric Deutsch - , Institut Gustave Roussy (Autor:in)
  • Pauline Wimberger - , Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe (Autor:in)
  • Jean Marc Classe - , René Gauducheau (Autor:in)
  • Noreen Gleeson - , Trinity College Dublin (Autor:in)
  • Heiko von der Leyen - , Hannover Clinical Trial Center GmbH (Autor:in)
  • Mathieu Minsat - , Institut Curie (Autor:in)
  • Coraline Dubot - , Institut Curie (Autor:in)
  • Pierre Gestraud - , Institut Curie (Autor:in)
  • Attila Kereszt - , SeqOmics Biotechnology Ltd. (Autor:in)
  • Istvan Nagy - , SeqOmics Biotechnology Ltd. (Autor:in)
  • Balazs Balint - , SeqOmics Biotechnology Ltd. (Autor:in)
  • Els Berns - , Erasmus University Rotterdam (Autor:in)
  • Ekaterina Jordanova - , Antoni van Leeuwenhoek Hospital (Autor:in)
  • Nicolas de Saint-Jorre - , Quanticsoft (Autor:in)
  • Alexia Savignoni - , Institut Curie (Autor:in)
  • Nicolas Servant - , Institut Curie (Autor:in)
  • Philippe Hupe - , Institut Curie (Autor:in)
  • Leanne de Koning - , Institut Curie (Autor:in)
  • Pierre Fumoleau - , Institut Curie (Autor:in)
  • Roman Rouzier - , Institut Curie (Autor:in)
  • Maud Kamal - , Institut Curie (Autor:in)

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.

Details

OriginalspracheEnglisch
Seiten (von - bis)253-260
Seitenumfang8
FachzeitschriftEBioMedicine
Jahrgang43
PublikationsstatusVeröffentlicht - Mai 2019
Peer-Review-StatusJa

Externe IDs

PubMed 30952619

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Bioraids study, Cervical cancers, Epigenetics pathways, Patient stratification, PI3KCA, Prospective database, Reverse phase protein array, Whole exome sequencing