title: Improved risk assessment of endometrial cancer by combined analysis of MSI, PI3K-AKT, Wnt/β-catenin and P53 pathway activation.
abstract: OBJECTIVE
  To investigate if analysis of genetic alterations in the main pathways involved in endometrioid type carcinogenesis (PI3K-AKT, Wnt/β-catenin, P53-activation and MSI) improves the current risk assessment based on clinicopathological factors.
  
  
  METHODS
  Formalin fixed paraffin embedded (FFPE) primary tumor samples of 65 patients with FIGO-stage I endometrioid type endometrial cancer (EEC) were selected from the randomized PORTEC-2 trial. Tumors were stained by immunohistochemistry for P53, PTEN and β-catenin. Tumor DNA was isolated for sequence analysis of TP53 (exons 4 to 8), hotspot mutation analysis of KRAS (exon 1) and PI3K (exon 9 and 20) and microsatellite-instability (MSI) analysis including MLH1 promotor-methylation status. Univariate and multivariate analyses for disease-free survival (DFS) using Cox regression models were performed.
  
  
  RESULTS
  P53 status (HR 6.7, 95%CI 1.75-26.0, p=0.006) and MSI were the strongest single genetic prognostic factors for decreased DFS, while high PI3K-AKT pathway activation showed a trend and β-catenin was not prognostic. The combination of multiple activated pathways was the most powerful prognostic factor for decreased DFS (HR 5.0; 95%CI 1.59-15.6 p=0.006). Multiple pathway activation, found in 8% of patients, was strongly associated with aggressive clinical course. In contrast, 40% of patients had no alterations in the investigated pathways and had a very low risk of disease progression.
  
  
  CONCLUSIONS
  Activation of multiple oncogenic pathways in EEC was the most powerful prognostic factor for decreased DFS, resulting in an individual risk assessment superior to the current approach based on clinicopathological factors.
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, The Netherlands. r.a.nout@lumc.nl
authors.forename: Remi A
authors.initials: RA
authors.lastname: Nout
authors.forename: Tjalling
authors.initials: T
authors.lastname: Bosse
authors.forename: Carien L
authors.initials: CL
authors.lastname: Creutzberg
authors.forename: Ina M
authors.initials: IM
authors.lastname: Jürgenliemk-Schulz
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Jobsen
authors.forename: Ludy C H W
authors.initials: LC
authors.lastname: Lutgens
authors.forename: Elzbieta M
authors.initials: EM
authors.lastname: van der Steen-Banasik
authors.forename: Ronald
authors.initials: R
authors.lastname: van Eijk
authors.forename: Natalja T
authors.initials: NT
authors.lastname: Ter Haar
authors.forename: Vincent T H B M
authors.initials: VT
authors.lastname: Smit
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008745:Methylation; D053842:Microsatellite Instability; D008875:Middle Aged; D015999:Multivariate Analysis; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D018570:Risk Assessment; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C117307:KRAS protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000070957:MutL Protein Homolog 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins