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. 2020 Nov:61:103049.
doi: 10.1016/j.ebiom.2020.103049. Epub 2020 Oct 20.

Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer

Suzy M Scholl  1 , Jonas Beal  2 , Leanne de Koning  3 , Elodie Girard  2 , Marina Popovic  4 , Anne de la Rochefordière  5 , Fabrice Lecuru  6 , Virginie Fourchotte  6 , Charlotte Ngo  7 , Anne Floquet  8 , Els Mjj Berns  9 , Gemma Kenter  10 , Pierre Gestraud  2 , Heiko von der Leyen  11 , Charlotte Lecerf  12 , Vincent Puard  3 , Sergio Roman Roman  3 , Aurelien Latouche  13 , Attila Kereszt  14 , Balazs Balint  15 , Roman Rouzier  16 , Maud Kamal  12
Affiliations

Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer

Suzy M Scholl et al. EBioMedicine. 2020 Nov.

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.

Keywords: Beta-catenin pβ-cat552 and pβ-cat675; Cervical cancer; Molecular and protein biomarkers for chemo-radiation efficiency; Molecular landscape.

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Conflict of interest statement

Declaration of Interests All authors report no conflict of interest.

Figures

Fig 1:
Fig. 1
Venn diagram illustrating the number of patients for the different combinations of omics types and clinical data. (CNV = copy number variation; RPPA = reverse phase protein array).
Fig 2:
Fig. 2
Coefficient values in Cox boost of frequent genetic variants associated with worse or better prognosis using all available omics types (mutational, copy number variation and RRPA variables) clinical data (panel a); clinical data with RPPA variables (panel b); gene and copy number variants and mutations (panel c) and mutations only (panel d). (mut = mutations; CNV = copy number variations; RPPA = reverse phase protein array).
Fig 3:
Fig. 3
Expression levels of phosphobeta-catenin-Ser552 (panel a) and 14–3–3 protein (panel b), IDO (panel c) and phosphobeta-catenin-Ser675 (panel d) per RPPA cluster.
Fig 4:
Fig. 4
Kaplan Meier progression free survival curves as a function of tumour heterogeneity at start (number of mutations per patients from a defined list of genes), limited to the following molecular alterations that were detected in a sizable proportion of patients (>5%). The probability of survival is the probability that the members of each group did not experience death or relapse at each time point.
Fig 5:
Fig. 5
Pattern of frequencies of molecular alterations of significance by individual patient. Panel a with mutations only and Panel b integrating mutations and CNV.
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