title: Strong correlation between molecular changes in endometrial carcinomas and concomitant hyperplasia.
abstract: OBJECTIVE
  Endometrial cancer (EC) results from the accumulation of numerous genetic abnormalities contributing to the progression from hyperplasia to EC. Information on these various genetic changes has been primarily derived from studying groups of either hyperplasias or cancers.We evaluated both hyperplastic and EC tissue obtained from the same surgical specimens for KRAS mutations, microsatellite instability (MSI), and mismatch repair gene methylation, and results were correlated between the paired hyperplastic tissue and EC. The aim was to determine if molecular alterations appearing in ECs might also be present in the premalignant (hyperplastic) region of the tumor.
  
  
  METHODS
  One hundred ninety-seven cases of EC with associated hyperplasia were evaluated. DNA samples were studied using primer sets for KRAS gene codons 12/13 and for MSI utilizing the Bethesda panel. Methylation testing was performed on specimens that were microsatellite unstable using the MRC Holland SALSA MS-MLPA methylation-specific DNA detection kit.
  
  
  RESULTS
  Forty-one (20.8%) of 197 cancers demonstrated a KRAS mutation, with 35 (85.4%) of 41 accompanying hyperplasias also containing a KRAS mutation. Forty-five cancers (22.8%) were microsatellite unstable, with 38 (84.4%) of 45 accompanying hyperplasias also demonstrating instability. Of the 45 microsatellite unstable cancers, 28 (62.2%) demonstrated methylation in both the cancer and the accompanying hyperplasia, whereas 9 pairs (20%) showed no methylation for either the cancer or hyperplasia.
  
  
  CONCLUSIONS
  Approximately 95% of endometrial specimens demonstrated identical molecular findings regarding KRAS mutation and microsatellite stability in the paired cancer and hyperplastic tissue. The same methylation pattern was found in 82.2% of the studied paired samples. Our findings strongly suggest that the molecular changes of KRAS mutation, MSI, and methylation occur early in the neoplastic process. We propose that endometrial biopsies revealing only hyperplasia should be studied for these molecular alterations as an indicator of possible early carcinogenesis.
authors.affiliation: Departments of *Medicine, †Obstetrics and Gynecology, and ‡Pathology, Saint Barnabas Medical Center, Livingston, NJ.
authors.forename: Peter
authors.initials: P
authors.lastname: Zauber
authors.forename: Thad R
authors.initials: TR
authors.lastname: Denehy
authors.forename: Robert R
authors.initials: RR
authors.lastname: Taylor
authors.forename: Emelie H
authors.initials: EH
authors.lastname: Ongcapin
authors.forename: Stephen
authors.initials: S
authors.lastname: Marotta
authors.forename: Marlene
authors.initials: M
authors.lastname: Sabbath-Solitare
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004714:Endometrial Hyperplasia / Q000235:genetics / Q000473:pathology*; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)