title: Molecular analysis of endometrial tumorigenesis: importance of complex hyperplasia regardless of atypia.
abstract: OBJECTIVE
  Endometrial carcinoma (EC) is common in the population and the most frequent extracolonic malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC)/Lynch syndrome. We characterized precursor lesions of endometrioid EC to identify markers of malignant transformation and tumor progression.
  
  
  METHODS
  Serial specimens of normal endometrium, simple hyperplasia, complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma obtained during a 10-year surveillance of DNA mismatch repair (MMR) gene mutation carriers (together 110 samples) were molecularly profiled and compared with a sporadic reference series of endometrial specimens taken for nonmalignant reasons (62 samples).
  
  
  RESULTS
  Among MMR gene mutation carriers, decreased MMR protein expression was present in 7% in normal endometrium, 40% in simple hyperplasia, 100% in complex hyperplasia without atypia, 92% in complex hyperplasia with atypia, and 100% in endometrial carcinoma. Microsatellite instability frequencies were lower (6%, 17%, 67%, 38%, and 64%, respectively). Among 24 tumor suppressor genes, the number of methylated loci increased from normal endometrium to simple hyperplasia to complex hyperplasia (complex hyperplasia without atypia/complex hyperplasia with atypia) in both Lynch syndrome and reference series. The most frequently methylated genes were CDH13, RASSF1A, and GSTP1. In MMR gene mutation carriers, MMR and methylation defects appeared up to 12 years before endometrial carcinoma.
  
  
  CONCLUSIONS
  Molecular changes in endometrial tissue are detectable several years before endometrial carcinoma in genetically predisposed individuals. Abnormal MMR and methylation classify normal endometrium and simple hyperplasia into one category and complex hyperplasia without atypia, complex hyperplasia with atypia, and endometrial carcinoma into another, suggesting that, contrary to a traditional view, complex hyperplasia without atypia and complex hyperplasia with atypia are equally important as precursor lesions of endometrial carcinoma.
authors.affiliation: Department of Medical Genetics, University of Helsinki, Helsinki, Finland. taina.nieminen@helsinki.fi
authors.forename: Taina T
authors.initials: TT
authors.lastname: Nieminen
authors.forename: Annette
authors.initials: A
authors.lastname: Gylling
authors.forename: Wael M
authors.initials: WM
authors.lastname: Abdel-Rahman
authors.forename: Kyösti
authors.initials: K
authors.lastname: Nuorva
authors.forename: Markku
authors.initials: M
authors.lastname: Aarnio
authors.forename: Laura
authors.initials: L
authors.lastname: Renkonen-Sinisalo
authors.forename: Heikki J
authors.initials: HJ
authors.lastname: Järvinen
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Ralf
authors.initials: R
authors.lastname: Bützow
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D006965:Hyperplasia; D008745:Methylation; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D014408:Biomarkers, Tumor