title: Beside P53 and PTEN: Identification of molecular alterations of the RAS/MAPK and PI3K/AKT signaling pathways in high-grade serous ovarian carcinomas to determine potential novel therapeutic targets.
abstract: Despite great histological and molecular heterogeneity, the clinical management of high-grade ovarian carcinomas remains unspecialized. As a major subgroup, high-grade serous ovarian carcinomas (HGSOCs) require novel therapies. In addition to utilizing conventional histological prognostic markers and performing oncogenetic investigations, the molecular diagnostic method of next generation sequencing (NGS) was performed to identify 'druggable' targets that could provide access to innovative therapy. The present study was performed in 45 HGSOC patients (mean age, 59.1 years; range, 25-87 years) with histologically proven HGSOC. Breast cancer 1/2 (BRCA1/2) germline mutations were screened in 17 patients with a familial or personal history of cancer, which was justified by oncogenetic investigations. Tumor protein 53 (P53) and phosphatase and tensin homolog (PTEN) expression were assessed in formalin-fixed paraffin-embedded tissues using immunohistochemistry. Somatic mutations of Kirsten rat sarcoma viral oncogene homolog, neuroblastoma RAS viral oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and MET proto-oncogene, receptor tyrosine kinase (MET) were screened using NGS on DNA extracts from frozen tumor specimens obtained at diagnosis. With a median follow-up of 38 months (range, 6-93 months), 20 patients are alive, 10 patients are disease-free and 14 patients progressed within 6 months following platinum-based therapy. P53 overexpression was detected in 67% of patients and PTEN loss was detected in 38% of the patients. The overexpression of mutant P53 was found to be associated with a longer progression-free and overall survival. In total, 2NRAS(exon 3), 3PIK3CA(exon 5 and 10) and 5METmutations (exons 14 and 18) were detected. In HGSOCs, in addition to P53 and PTEN alterations, somatic genetic abnormalities can be detected using NGS and provide molecular rationale for targeted therapies, potentially offering novel therapeutic opportunities to patients.
authors.affiliation: Faculty of Pharmacy, Université de Lorraine, 54001 Nancy, France; CNRS UMR 7039 CRAN, Université de Lorraine, 54506 Vandoeuvre-les-Nancy, France; Department of Biopathology, Institut de Cancérologie de Lorraine, 54519 Vandoeuvre-les-Nancy, France; Department of Gynecological Oncology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei 430071, P.R. China.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Chen
authors.affiliation: Faculty of Pharmacy, Université de Lorraine, 54001 Nancy, France.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cavazza
authors.affiliation: Faculty of Pharmacy, Université de Lorraine, 54001 Nancy, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Barlier
authors.affiliation: Department of Data Biostatistics, Institut de Cancérologie de Lorraine, 54519 Vandoeuvre-les-Nancy, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Salleron
authors.affiliation: Faculty of Pharmacy, Université de Lorraine, 54001 Nancy, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Filhine-Tresarrieu
authors.affiliation: Department of Medical Oncology, Institut de Cancérologie de Lorraine, 54519 Vandoeuvre-les-Nancy, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Gavoilles
authors.affiliation: Faculty of Pharmacy, Université de Lorraine, 54001 Nancy, France; CNRS UMR 7039 CRAN, Université de Lorraine, 54506 Vandoeuvre-les-Nancy, France; Department of Biopathology, Institut de Cancérologie de Lorraine, 54519 Vandoeuvre-les-Nancy, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Merlin
authors.affiliation: Faculty of Pharmacy, Université de Lorraine, 54001 Nancy, France; CNRS UMR 7039 CRAN, Université de Lorraine, 54506 Vandoeuvre-les-Nancy, France; Department of Biopathology, Institut de Cancérologie de Lorraine, 54519 Vandoeuvre-les-Nancy, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Harlé
keywords: high resolution melting-polymerase chain reaction; high-grade serous ovarian carcinoma; immunohistochemistry; next generation sequencing; signaling pathway; targeted therapy