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

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.

Analysis of systemic inflammatory and coagulation biomarkers in advanced cervical cancer: Prognostic and predictive significance

“…In recent years, many genetic, laboratory, clinical, and pathological studies have examined the prognostic factors of cervical cancer. [10][11][12] In recent studies, a large number of clinical indicators such as race, age, histological type, grade, and tumor volume seemed to be associated with prognosis. 13 In our study, age, tumor size, and grade were not correlated with prognosis.…”

Clinicopathological Significance of ATRX Expression in Nasopharyngeal Carcinoma Patients: A Retrospective Study

“…The prognostic significance of ATRX mutation on cancer patients varies between researches. It is reported that ATRX mutation is a poor prognostic factor in pancreatic neuroendocrine tumors (pNETs) 20 , hepatic angiosarcomas 21 , and leiomyosarcoma 22 , 23 , while it is found to be a good prognostic factor in glioma 24 , and cervical cancer 13 . Such complexities without universal good prognosis may suggest that mutations affecting chromatin remodeling genes or expression altering chromatin remodeling proteins do not directly determine the aggressiveness or prognosis of malignancies 16 .…”

“…However, the data on the incidence of ATRX expression and clinical significance in epithelial carcinomas is limited. It is reported that ATRX loss predicts good prognosis in cervical carcinoma and hepatocarcinoma 13 , 14 . And ATRX mutation results in increased immune checkpoint inhibitor (ICI) sensitivity in NSCLC 12 .…”

Multicenter reverse-phase protein array data integration

“…The technology offers precise and sensitive multiplexed quantification of the abundance of proteins and posttranslational modifications in hundreds of arrayed samples, providing the opportunity for high-throughput proteomic profiling of cells and tissues [13][14][15] . RPPA therefore provides a valuable tool for the targeted analysis of disease-relevant signaling mechanisms, including in cancer [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] .…”