title: Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes.
abstract: Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ~74,000 deaths annually. Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology. We used whole-exome sequencing to comprehensively search for somatic mutations within ~22,000 protein-encoding genes in 13 primary serous endometrial tumors. We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors. We identified high frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%). Overall, 36.5% of serous tumors had a mutated chromatin-remodeling gene, and 35% had a mutated ubiquitin ligase complex gene, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.
authors.affiliation: Cancer Genetics Branch, National Human Genome Research Institute, US National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Le Gallo
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: O'Hara
authors.forename: Meghan L
authors.initials: ML
authors.lastname: Rudd
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Urick
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Hansen
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: O'Neil
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Price
authors.forename: Suiyuan
authors.initials: S
authors.lastname: Zhang
authors.forename: Bryant M
authors.initials: BM
authors.lastname: England
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.forename: Philip
authors.initials: P
authors.lastname: Hieter
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.forename: Daphne W
authors.initials: DW
authors.lastname: Bell
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D018262:Adenocarcinoma, Clear Cell / Q000235:genetics*; D000328:Adult; D001324:Autoantigens / Q000235:genetics; D001483:Base Sequence; D018269:Carcinoma, Endometrioid / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D005787:Gene Frequency; D006801:Humans; D048768:MAP Kinase Kinase Kinase 4 / Q000235:genetics; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011955:Receptors, Drug / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D064233:Sulfonylurea Receptors; D014157:Transcription Factors / Q000235:genetics; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: C577510:ABCC9 protein, human; C112476:ARID1A protein, human; D018528:ATP-Binding Cassette Transporters; D001324:Autoantigens; C115323:CHD4 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D009687:Nuclear Proteins; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D012097:Repressor Proteins; C509761:SPOP protein, human; D064233:Sulfonylurea Receptors; D014157:Transcription Factors; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases; D048768:MAP Kinase Kinase Kinase 4; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex