Impact of β-catenin phosphorylation patterns on tumour control/progression in a prospective cervical cancer study (RAIDs)

Abstract

Abstract Background Between 2013 and 2017, the RAIDs consortium conducted a European biobanking study, [BioRAIDs (NCT02428842)] aiming at prospectively annotating cervical cancer (CC) patients and identifying molecular patterns associated with outcome. Dominant oncogenic alterations were reported in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). A “metagene” combining these alterations was associated with outcome ( https://doi.org/10.1016/j.ebiom.2019.03.069 ). Methods WES and RPPA data together with PFS at 24 months are available in 89 patients. A boosting approach based on a solid theoretical framework, able to cope with high-dimensional data and censored survival end-points, allowed the identification of innovative potential prognostic markers. Results At a median follow up (FU) of 24 months, progression-free survival (PFS) rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were 65.4% [CI95%: 60.2-71.1]. In the present analysis, beyond viral clade and FIGO stage, a number of RPPA phospho-protein parameters came up as relevant predictors, associated with better or poorer outcome. Of particular interest is the detection of two different sites for β-catenin phosphorylation (at serine residues 552 and 675), which were associated with prediction of extremes of positive or negative outcome. Conclusions Proteasome-dependant posttranslational modifications to a low molecular weight form of β-catenin phophorylated at COOH-terminal residue S552 has been shown to enhance nuclear translocation and β-catenin/TCF reporter activation possibly through association with histone acetylases (doi: 10.1038/s41598-017-18421-8). Phospho-β-catenin S552 and S675 may predict CC tumor control/progression in patients who failed DNA repair pathway inhibition. Ongoing studies attempt to better define the role of different β-catenin phosphorylations and molecular forms in the BioRAIDS population. Clinical trial identification NCT02428842. Legal entity responsible for the study Institut Curie. Funding The European Union’s Seventh Program for Research, Technological Development and Demonstration under Grant agreement No 304810 and the Fondation ARC pour la Recherche Contre le Cancer. Disclosure All authors have declared no conflicts of interest.