title: Identification of potential therapeutic targets by molecular profiling of 628 cases of uterine serous carcinoma.
abstract: BACKGROUND
  Therapeutic options are limited for uterine serous carcinoma (USC). TP53, PIK3CA, FBXW7, and ERBB mutations, as well as HER2 and EGFR overexpression have been reported. We aim to evaluate patterns of molecular, genomic and protein changes in 628USC tumors.
  
  
  METHODS
  628 consecutive cases of USC submitted to Caris Life Sciences from Mar, 2011 to July, 2014 were reviewed. These were analyzed using the Illumina TruSeq Amplcon Cancer panel to search for sequenced variants in 47 genes commonly implicated in carcinomatosis. In situ hybridization and immunohistochemistry were also used to assess copy number and protein expression, respectively, of selected genes.
  
  
  RESULTS
  31 out of 47 genes of interest harbored mutations, including TP53 (76%), PIK3CA (29%), FBXW7 (12%) and KRAS (9.3%). BRCA1 and BRCA2 were mutated in 9.1% and 6.3%, respectively. ERCC1 and MGMT were absent in 81% and 46% of tumors analyzed, respectively, suggesting potential benefit from platinum and alkylating agents. While not traditionally considered hormone-dependent, our cohort showed high ERα (60%), PR (32%), and AR (27%) expression. HER2 overexpression was 10% via IHC, amplification was 17% via CISH/FISH and mutation was 2% via NGS. While low in PTEN mutation frequency (7%), 45% of USC showed PTEN loss on IHC, and 29% harbored PIK3A mutation, suggesting deregulation of P13K/AKT pathway in a subset of patients. 11% expressed PDL1 and 67% expressed PD1.
  
  
  CONCLUSIONS
  Our findings suggest hormonal receptors, as well as genes implicated in DNA repair, cell proliferation and cell cycle pathways are of interest in USC.
authors.affiliation: Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, United States.
authors.forename: Nathaniel L
authors.initials: NL
authors.lastname: Jones
authors.affiliation: Caris Life Sciences, United States.
authors.forename: Joanne
authors.initials: J
authors.lastname: Xiu
authors.affiliation: Caris Life Sciences, United States.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Reddy
authors.affiliation: Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, United States.
authors.forename: William M
authors.initials: WM
authors.lastname: Burke
authors.affiliation: Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, United States.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Tergas
authors.affiliation: Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, United States.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Wright
authors.affiliation: Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, United States. Electronic address: jh3558@cumc.columbia.edu.
authors.forename: June Y
authors.initials: JY
authors.lastname: Hou
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology
keywords: Carcinoma; Endometrial; Genomic; Molecular; Serous; Uterine