Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes

Nat Genet. 2012 Dec;44(12):1310-5. doi: 10.1038/ng.2455. Epub 2012 Oct 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Adenocarcinoma, Clear Cell / genetics*
  • Adult
  • Autoantigens / genetics
  • Base Sequence
  • Carcinoma, Endometrioid / genetics*
  • Cell Cycle Proteins / genetics
  • Chromatin Assembly and Disassembly / genetics*
  • E1A-Associated p300 Protein / genetics
  • Endometrial Neoplasms / genetics*
  • Exome / genetics*
  • F-Box Proteins / genetics
  • F-Box-WD Repeat-Containing Protein 7
  • Female
  • Gene Frequency
  • Humans
  • MAP Kinase Kinase Kinase 4 / genetics
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins / genetics
  • Potassium Channels, Inwardly Rectifying / genetics
  • Receptors, Drug / genetics
  • Repressor Proteins / genetics
  • Sequence Analysis, DNA
  • Sulfonylurea Receptors
  • Transcription Factors / genetics
  • Ubiquitin-Protein Ligase Complexes / genetics*
  • Ubiquitin-Protein Ligases / genetics

Substances

  • ABCC9 protein, human
  • ARID1A protein, human
  • ATP-Binding Cassette Transporters
  • Autoantigens
  • CHD4 protein, human
  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • Nuclear Proteins
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Drug
  • Repressor Proteins
  • SPOP protein, human
  • Sulfonylurea Receptors
  • Transcription Factors
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Ubiquitin-Protein Ligase Complexes
  • Ubiquitin-Protein Ligases
  • MAP Kinase Kinase Kinase 4
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex