Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer
Suzy M Scholl,
Jonas Beal,
Leanne de Koning,
Elodie Girard,
Marina Popovic,
Anne de la Rochefordière,
Fabrice Lecuru,
Virginie Fourchotte,
Charlotte Ngo,
Anne Floquet,
Els MJJ Berns,
Gemma Kenter,
Pierre Gestraud,
Heiko von der Leyen,
Charlotte Lecerf,
Vincent Puard,
Sergio Roman Roman,
Aurelien Latouche,
Attila Kereszt,
Balazs Balint,
Roman Rouzier,
Maud Kamal
Affiliations
Suzy M Scholl
Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France; Corresponding author: Suzy Scholl, Institut Curie, Department of Drug Development and Innovation (D3i), 26 Rue d'Ulm, Paris 75005,
Jonas Beal
Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, 75005 Paris, France
Leanne de Koning
Department of Translational Research, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France
Elodie Girard
Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, 75005 Paris, France
Marina Popovic
Oncology Institute of Vojvodina, Put doktora Goldmana, 421204 Sremska Kamenica, Serbia
Anne de la Rochefordière
Department of Radiotherapy, Institut Curie, PSL Research University, 75005 Paris, France
Fabrice Lecuru
Department of Surgery, Institut Curie, PSL Research University, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France
Virginie Fourchotte
Department of Surgery, Institut Curie, PSL Research University, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France
Charlotte Ngo
Service de chirurgie cancérologique gynécologique et du sein, Hôpital Européen Georges Pompidou, APHP et faculté de médecine, Université Paris Descartes, France
Anne Floquet
Chirurgie onco-gynécologique and Oncology, Institut Bergonié, Centre Régional de Lutte contre le Cancer Bordeaux-Aquitaine, France
Els MJJ Berns
Dept Medical Oncology, Erasmus MC, 3000 CA Rotterdam, Netherlands
Gemma Kenter
Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France; Department of Gynaecologic Oncology Amsterdam, Amsterdam UMC and The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
Pierre Gestraud
Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, 75005 Paris, France
Heiko von der Leyen
Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France; Hannover Clinical Trial Center, Hannover Medical School Germany
Charlotte Lecerf
Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France
Vincent Puard
Department of Translational Research, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France
Sergio Roman Roman
Department of Translational Research, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France
Aurelien Latouche
Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, 75005 Paris, France; Conservatoire national des arts et métiers, Paris, France
Attila Kereszt
Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France; SeqOmics Biotechnology Ltd, Vallalkozok utja 7, Morahalom, Hungary
Balazs Balint
Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France; Department of Translational Research, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France
Roman Rouzier
Department of Surgery, Institut Curie, PSL Research University, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France; Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, 75005 Paris, France
Maud Kamal
Department of Drug Development and Innovation, Institut Curie, PSL Research University, 75005 Paris & 92210 Saint-Cloud, France
ABSTRACT: BACKGROUND: Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality world wide and constitutes the third most common malignancy in women. The RAIDs consortium (http://www.raids-fp7.eu/) conducted a prospective European study [BioRAIDs (NCT02428842)] with the objective to stratify CC patients for innovative treatments. A “metagene” of genomic markers in the PI3K pathway and epigenetic regulators had been previously associated with poor outcome [2]. METHODS: To detect new, more specific, targets for treatment of patients who resist standard chemo-radiation, a high-dimensional Cox model was applied to define dominant molecular variants, copy number variations, and reverse phase protein arrays (RPPA). FINDINGS: Survival analysis on 89 patients with all omics data available, suggested loss-of-function (LOF) or activating molecular alterations in nine genes to be candidate biomarkers for worse prognosis in patients treated by chemo-radiation while LOF of ATRX, MED13 as well as CASP8 were associated with better prognosis. When protein expression data by RPPA were factored in, the supposedly low molecular weight and nuclear form, of beta-catenin, phosphorylated in Ser552 (pβ-Cat552), ranked highest for good prognosis, while pβ-Cat675 was associated with worse prognosis. INTERPRETATION: These findings call for molecularly targeted treatments involving p53, Wnt pathway, PI3K pathway, and epigenetic regulator genes. Pβ-Cat552 and pβ-Cat675 may be useful biomarkers to predict outcome to chemo-radiation, which targets the DNA repair axis. FUNDING: European Union's Seventh Program for research, technological development and demonstration (agreement N°304,810), the Fondation ARC pour la recherche contre le cancer.
