title: High-throughput interrogation of PIK3CA, PTEN, KRAS, FBXW7 and TP53 mutations in primary endometrial carcinoma.
abstract: OBJECTIVE
  Endometrial cancer patients may benefit from systemic adjuvant chemotherapy, alone or in combination with targeted therapies. Prognostic and predictive markers are needed, however, to identify patients amenable for these therapies.
  
  
  METHODS
  Primary endometrial tumors were genotyped for >100 hot spot mutations in genes potentially acting as prognostic or predictive markers. Mutations were correlated with tumor characteristics in a discovery cohort, replicated in independent cohorts and finally, confirmed in the overall population (n=1063).
  
  
  RESULTS
  PIK3CA, PTEN and KRAS mutations were most frequently detected, respectively in 172 (16.2%), 164 (15.4%) and 161 (15.1%) tumors. Binary logistic regression revealed that PIK3CA mutations were more common in high-grade tumors (OR=2.03; P=0.001 for grade 2 and OR=1.89; P=0.012 for grade 3 compared to grade 1), whereas a positive TP53 status correlated with type II tumors (OR=11.92; P<0.001) and PTEN mutations with type I tumors (OR=19.58; P=0.003). Conversely, FBXW7 mutations correlated with positive lymph nodes (OR=3.38; P=0.045). When assessing the effects of individual hot spot mutations, the H1047R mutation in PIK3CA correlated with high tumor grade and reduced relapse-free survival (HR=2.18; P=0.028).
  
  
  CONCLUSIONS
  Mutations in PIK3CA, TP53, PTEN and FBXW7 correlate with high tumor grade, endometrial cancer type and lymph node status, whereas PIK3CA H1047R mutations serve as prognostic markers for relapse-free survival in endometrial cancer patients.
authors.affiliation: Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, University Hospitals Gasthuisberg, Leuven, Belgium.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Garcia-Dios
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Lieve
authors.initials: L
authors.lastname: Coenegrachts
authors.forename: Ingrid
authors.initials: I
authors.lastname: Vandenput
authors.forename: An
authors.initials: A
authors.lastname: Capoen
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Webb
authors.forename: Kaltin
authors.initials: K
authors.lastname: Ferguson
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.forename: Bart
authors.initials: B
authors.lastname: Claes
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.forename: Philippe
authors.initials: P
authors.lastname: Moerman
authors.forename: Johan
authors.initials: J
authors.lastname: Van Robays
authors.forename: Janusz
authors.initials: J
authors.lastname: Marcickiewicz
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins