title: Histo-genomic stratification reveals the frequent amplification/overexpression of CCNE1 and BRD4 genes in non-BRCAness high grade ovarian carcinoma.
abstract: The treatment of epithelial ovarian cancer (EOC) is narrowly focused despite the heterogeneity of this disease in which outcomes remain poor. To stratify EOC patients for targeted therapy, we developed an approach integrating expression and genomic analyses including the BRCAness status. Gene expression and genomic profiling were used to identify genes recurrently (>5%) amplified and overexpressed in 105 EOC. The LST (Large-scale State Transition) genomic signature of BRCAness was applied to define molecular subgroups of EOC. Amplified/overexpressed genes clustered mainly in 3q, 8q, 19p and 19q. These changes were generally found mutually exclusive. In the 85 patients for which the genomic signature could be determined, genomic BRCAness was found in 52 cases (61.1%) and non-BRCAness in 33 (38.8%). A striking mutual exclusivity was observed between BRCAness and amplification/overexpression data. Whereas 3q and 8q alterations were preferentially observed in BRCAness EOC, most alterations on chromosome 19 were in non-BRCAness cases. CCNE1 (19q12) and BRD4 (19p13.1) amplification/overexpression was found in 19/33 (57.5%) of non-BRCAness cases. Such disequilibrium was also found in the TCGA EOC data set used for validation. Potential target genes are frequently amplified/overexpressed in non-BRCAness EOC. We report that BRD4, already identified as a target in several tumor models, is a new potential target in high grade non-BRCAness ovarian carcinoma.
authors.affiliation: Department of Biopathology, Institut Curie, Paris, France.|EA4340-BCOH, Versailles Saint-Quentin-en-Yvelines University, Guyancourt, France.|Department of Translational Research, Institut Curie, Paris, France.
authors.forename: Oumou
authors.initials: O
authors.lastname: Goundiam
authors.affiliation: Bioinformatics and Computational Systems Biology of Cancer, Institut Curie, Paris, France.|Mines Paris Tech, Paris, France.|Inserm U900, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gestraud
authors.affiliation: Inserm U830 Institut Curie, Paris, France.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Popova
authors.affiliation: Department of Medical Oncology, Institut Curie, Paris, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: De la Motte Rouge
authors.affiliation: Department of Surgery, and on behalf of the Gynecologic Study Group, Institut Curie, Paris, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Fourchotte
authors.affiliation: Department of Translational Research, Institut Curie, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Gentien
authors.affiliation: Bioinformatics and Computational Systems Biology of Cancer, Institut Curie, Paris, France.|Mines Paris Tech, Paris, France.|Inserm U900, Paris, France.|CNRS UMR 144.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hupé
authors.affiliation: Department of Biopathology, Institut Curie, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Becette
authors.affiliation: Department of Biopathology, Institut Curie, Paris, France.|Inserm U830 Institut Curie, Paris, France.|Université Paris Descartes, Sciences Pharmaceutiques et Biologiques, Sorbonne Paris Cité, Paris, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Houdayer
authors.affiliation: Department of Translational Research, Institut Curie, Paris, France.
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.affiliation: Department of Biopathology, Institut Curie, Paris, France.|Inserm U830 Institut Curie, Paris, France.
authors.forename: Marc-Henri
authors.initials: MH
authors.lastname: Stern
authors.affiliation: Department of Biopathology, Institut Curie, Paris, France.|EA4340-BCOH, Versailles Saint-Quentin-en-Yvelines University, Guyancourt, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sastre-Garau
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D018797:Cell Cycle Proteins; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D019927:Cyclin E / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics*; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C475820:CCNE1 protein, human
keywords: BRCAness; BRD4; CCNE1; genomics; ovarian cancer