TY - JOUR
T1 - Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer
AU - Scholl, Suzy M.
AU - Beal, Jonas
AU - de Koning, Leanne
AU - Girard, Elodie
AU - Popovic, Marina
AU - de la Rochefordière, Anne
AU - Lecuru, Fabrice
AU - Fourchotte, Virginie
AU - Ngo, Charlotte
AU - Floquet, Anne
AU - Berns, Els MJJ
AU - Kenter, Gemma
AU - Gestraud, Pierre
AU - von der Leyen, Heiko
AU - Lecerf, Charlotte
AU - Puard, Vincent
AU - Roman, Sergio Roman
AU - Latouche, Aurelien
AU - Kereszt, Attila
AU - Balint, Balazs
AU - Rouzier, Roman
AU - Kamal, Maud
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
KW - Beta-catenin pβ-cat552 and pβ-cat675
KW - Cervical cancer
KW - Molecular and protein biomarkers for chemo-radiation efficiency
KW - Molecular landscape
UR - http://www.scopus.com/inward/record.url?scp=85092895744&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2020.103049
DO - 10.1016/j.ebiom.2020.103049
M3 - Article
C2 - 33096476
AN - SCOPUS:85092895744
VL - 61
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
M1 - 103049
ER -