title: Early telomere shortening and genomic instability in tubo-ovarian preneoplastic lesions.
abstract: OBJECTIVE
  Genetic instability plays an important role in ovarian carcinogenesis. We investigated the level of telomere shortening and genomic instability in early and preinvasive stages of ovarian cancer, serous tubal intraepithelial carcinoma (STIC), and tubo-ovarian dysplasia (TOD).
  
  
  METHODS
  Fifty-one TOD from prophylactic salpingo-oophorectomies with BRCA1 or 2 mutation, 12 STICs, 53 tubo-ovarian high-grade serous carcinoma, and 36 noncancerous controls were laser capture microdissected from formalin-fixed, paraffin-embedded sections, analyzed by comparative genomic hybridization (array CGH) and for telomere length (using quantitative real-time PCR based on the Cawthon's method). TOD and STICs were defined by morphologic scores and immunohistochemical expressions of p53, Ki67, and γH2AX.
  
  
  RESULTS
  TOD showed marked telomere shortening compared with noncancerous controls (P < 10(-7)). STICs had even shorter telomeres than TOD (P = 0.0008). Ovarian carcinoma had shorter telomeres than controls but longer than STICs and dysplasia. In TOD, telomeres were significantly shorter in those with BRCA1 mutation than in those with BRCA2 mutation (P = 0.005). In addition, γH2AX expression in TOD and STIC groups with short telomeres was significantly increased (P < 10(-7)). In dysplastic epithelium, we found subtle genomic alterations, in contrast to more important genomic imbalances in STICs. The total number of genetic alterations was the highest in ovarian cancers.
  
  
  CONCLUSIONS
  These findings suggest that genetic instability occurs in early stages of ovarian tumorigenesis. STICs and noninvasive dysplasia are likely an important step in early serous ovarian neoplasia.
authors.affiliation: Department of Histopathology, Centre Jean Perrin, ERTICA Research Team, Clermont-Ferrand, France. chenegautier@yahoo.fr
authors.forename: Gautier
authors.initials: G
authors.lastname: Chene
authors.forename: Andrei
authors.initials: A
authors.lastname: Tchirkov
authors.forename: Eleonore
authors.initials: E
authors.lastname: Pierre-Eymard
authors.forename: Jacques
authors.initials: J
authors.lastname: Dauplat
authors.forename: Ines
authors.initials: I
authors.lastname: Raoelfils
authors.forename: Anne
authors.initials: A
authors.lastname: Cayre
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Watkin
authors.forename: Philippe
authors.initials: P
authors.lastname: Vago
authors.forename: Frederique
authors.initials: F
authors.lastname: Penault-Llorca
mesh_terms: D055028:Comparative Genomic Hybridization; D005185:Fallopian Tube Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011230:Precancerous Conditions; D012189:Retrospective Studies; D016615:Telomere / Q000378:metabolism; D059506:Telomere Shortening; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D006657:Histones; D016159:Tumor Suppressor Protein p53