Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer.
Biomarkers, Tumor
Computational Biology
DNA Copy Number Variations
Disease Susceptibility
Female
Genetic Heterogeneity
Genetic Markers
Humans
Mutation
Neoplasm Staging
Phosphoproteins
/ genetics
Phosphorylation
Prognosis
Recurrence
Uterine Cervical Neoplasms
/ genetics
Exome Sequencing
beta Catenin
/ genetics
Beta-catenin pβ-cat552 and pβ-cat675
Cervical cancer
Molecular and protein biomarkers for chemo-radiation efficiency
Molecular landscape
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Nov 2020
Nov 2020
Historique:
received:
12
05
2020
revised:
10
07
2020
accepted:
21
09
2020
pubmed:
24
10
2020
medline:
5
8
2021
entrez:
23
10
2020
Statut:
ppublish
Résumé
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]. 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). 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. 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. European Union's Seventh Program for research, technological development and demonstration (agreement N°304,810), the Fondation ARC pour la recherche contre le cancer.
Sections du résumé
BACKGROUND
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
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
RESULTS
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
CONCLUSIONS
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
BACKGROUND
European Union's Seventh Program for research, technological development and demonstration (agreement N°304,810), the Fondation ARC pour la recherche contre le cancer.
Identifiants
pubmed: 33096476
pii: S2352-3964(20)30425-4
doi: 10.1016/j.ebiom.2020.103049
pmc: PMC7581879
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
CTNNB1 protein, human
0
Genetic Markers
0
Phosphoproteins
0
beta Catenin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
103049Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests All authors report no conflict of interest.
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