title: Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses.
abstract: BACKGROUND
  Uterine cancer is the fourth most common malignancy in women, and uterine serous carcinoma is the most aggressive subtype. However, the molecular pathogenesis of uterine serous carcinoma is largely unknown. We analyzed the genomes of uterine serous carcinoma samples to better understand the molecular genetic characteristics of this cancer.
  
  
  METHODS
  Whole-exome sequencing was performed on 10 uterine serous carcinomas and the matched normal blood or tissue samples. Somatically acquired sequence mutations were further verified by Sanger sequencing. The most frequent molecular genetic changes were further validated by Sanger sequencing in 66 additional uterine serous carcinomas and in nine serous endometrial intraepithelial carcinomas (the preinvasive precursor of uterine serous carcinoma) that were isolated by laser capture microdissection. In addition, gene copy number was characterized by single-nucleotide polymorphism (SNP) arrays in 23 uterine serous carcinomas, including 10 that were subjected to whole-exome sequencing.
  
  
  RESULTS
  We found frequent somatic mutations in TP53 (81.6%), PIK3CA (23.7%), FBXW7 (19.7%), and PPP2R1A (18.4%) among the 76 uterine serous carcinomas examined. All nine serous carcinomas that had an associated serous endometrial intraepithelial carcinoma had concordant PIK3CA, PPP2R1A, and TP53 mutation status between uterine serous carcinoma and the concurrent serous endometrial intraepithelial carcinoma component. DNA copy number analysis revealed frequent genomic amplification of the CCNE1 locus (which encodes cyclin E, a known substrate of FBXW7) and deletion of the FBXW7 locus. Among 23 uterine serous carcinomas that were subjected to SNP array analysis, seven tumors with FBXW7 mutations (four tumors with point mutations, three tumors with hemizygous deletions) did not have CCNE1 amplification, and 13 (57%) tumors had either a molecular genetic alteration in FBXW7 or CCNE1 amplification. Nearly half of these uterine serous carcinomas (48%) harbored PIK3CA mutation and/or PIK3CA amplification.
  
  
  CONCLUSIONS
  Molecular genetic aberrations involving the p53, cyclin E-FBXW7, and PI3K pathways represent major mechanisms in the development of uterine serous carcinoma.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Kuhn
authors.forename: Ren-Chin
authors.initials: RC
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Guan
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Song
authors.forename: Xiguo
authors.initials: X
authors.lastname: Yuan
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.forename: Richard B S
authors.initials: RB
authors.lastname: Roden
authors.forename: Kuan-Tin
authors.initials: KT
authors.lastname: Kuo
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakayama
authors.forename: Blaise
authors.initials: B
authors.lastname: Clarke
authors.forename: Patricia
authors.initials: P
authors.lastname: Shaw
authors.forename: Narciso
authors.initials: N
authors.lastname: Olvera
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kurman
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Levine
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
mesh_terms: D000328:Adult; D000368:Aged; D002278:Carcinoma in Situ / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics*; D019927:Cyclin E / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism*; D059472:Exome; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D018628:Gene Dosage; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054648:Protein Phosphatase 2 / Q000235:genetics; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: C475820:CCNE1 protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D015513:Oncogene Proteins; C517191:PPP2R1A protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D054648:Protein Phosphatase 2