title: Microsatellite instability and epigenetic inactivation of MLH1 and outcome of patients with endometrial carcinomas of the endometrioid type.
abstract: OBJECTIVE
  Most studies of microsatellite instability (MSI) and outcomes in endometrial cancer patients have included varied histologic subtypes. Nonetheless, MSI occurs almost exclusively in endometrioid tumors. The impact of MSI on outcomes in patients with endometrial cancer is controversial. We sought to determine whether MSI and MLH1 methylation are associated with clinicopathologic variables and survival outcomes in a large series of patients with endometrial carcinomas of the endometrioid type.
  
  
  METHODS
  Tumor samples, blood, and clinicopathologic data were prospectively collected and analyzed for 446 patients with endometrioid carcinomas. MSI was determined using five National Cancer Institute (NCI) consensus panel markers, and the methylation status of the MLH1 promoter was determined by combined bisulfite restriction analysis (COBRA). Associations with clinicopathologic variables and survival outcomes were evaluated.
  
  
  RESULTS
  MSI was identified in 147 cases (33%). MSI was associated with higher International Federation of Gynecology and Obstetrics (FIGO) grade (P < .0001). MSI+ tumors without MLH1 methylation were associated with younger age (P < .001). MSI was not associated with overall survival (OS; hazard ratio [HR], 1.011; 95% CI, 0.688 to 1.484; P = .96) or disease-free survival (DFS; HR 0.951; 95% CI, 0.554 to 1.635; P = .86). The combined MSI/MLH1 methylation status (treating MSI- as the reference) did not predict OS (MSI+/MLH1-U: HR, 0.62; 95% CI, 0.27 to 1.44; P = .26; MSI+/MLH1-M: HR, 0.95; 95% CI, 0.62 to 1.46; P = .82) or DFS (MSI+/MLH1-U: HR, 0.51; 95% CI, 0.22 to 1.19; P = .12; MSI+/MLH1-M: HR, 0.93; 95% CI, 0.62 to 1.40; P = .72).
  
  
  CONCLUSIONS
  MSI is not associated with survival in patients with endometrioid endometrial cancer.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St Louis, MO 63110, USA. zighelboimi@wustl.edu
authors.forename: Israel
authors.initials: I
authors.lastname: Zighelboim
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.forename: Randall K
authors.initials: RK
authors.lastname: Gibb
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Powell
authors.forename: Janet S
authors.initials: JS
authors.lastname: Rader
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D018269:Carcinoma, Endometrioid / Q000235:genetics*; D015331:Cohort Studies; D019175:DNA Methylation; D004260:DNA Repair; D016889:Endometrial Neoplasms / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011446:Prospective Studies
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein