title: Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers.
abstract: BACKGROUND
  PTEN tumor suppressor gene mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. Testing the hypothesis that altered PTEN function precedes the appearance of endometrial adenocarcinoma has been difficult, however, partly because of uncertainties in precancer diagnosis.
  
  
  METHODS
  Two series of endometrial cancer and precancer (endometrial intraepithelial neoplasia, as diagnosed by computerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and another for PTEN protein expression by immunohistochemistry. Endometria altered by high estrogen levels that are unopposed by progestins-conditions known to increase cancer risk-were also studied by immunohistochemistry. Fisher's exact test was used for statistical analysis.
  
  
  RESULTS
  The PTEN mutation rate was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (16 of 29) in precancers, and the difference in number of mutations was statistically significant (two-sided P =.025). No normal endometria showed PTEN mutations. Although most precancers and cancers had a mutation in only one PTEN allele, endometrioid endometrial adenocarcinomas showed complete loss of PTEN protein expression in 61% (20 of 33) of cases, and 97% (32 of 33) showed at least some diminution in expression. Cancers and most precancers exhibited contiguous groups of PTEN-negative glands, while endometria altered by unopposed estrogens showed isolated PTEN-negative glands.
  
  
  CONCLUSIONS
  Loss of PTEN function by mutational or other mechanisms is an early event in endometrial tumorigenesis that may occur in response to known endocrine risk factors and offers an informative immunohistochemical biomarker for premalignant disease. Individual PTEN-negative glands in estrogen-exposed endometria are the earliest recognizable stage of endometrial carcinogenesis. Proliferation into dense clusters that form discrete premalignant lesions follows.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. gmutter@rics.bwh.harvard.edu
authors.forename: G L
authors.initials: GL
authors.lastname: Mutter
authors.forename: M C
authors.initials: MC
authors.lastname: Lin
authors.forename: J T
authors.initials: JT
authors.lastname: Fitzgerald
authors.forename: J B
authors.initials: JB
authors.lastname: Kum
authors.forename: J P
authors.initials: JP
authors.lastname: Baak
authors.forename: J A
authors.initials: JA
authors.lastname: Lees
authors.forename: L P
authors.initials: LP
authors.lastname: Weng
authors.forename: C
authors.initials: C
authors.lastname: Eng
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D004252:DNA Mutational Analysis; D017931:DNA Primers; D003937:Diagnosis, Differential; D016889:Endometrial Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000175:diagnosis* / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human