title: DNA damage signaling and apoptosis in preinvasive tubal lesions of ovarian carcinoma.
abstract: OBJECTIVE
  High-grade serous ovarian cancer (HGSC) is the most life-threatening gynecological malignancy despite surgery and chemotherapy. A better understanding of the molecular basis of the preinvasive stages might be helpful in early detection and diagnosis. Genetic instability is 1 of the characteristics shared by most human cancers, and its level is variable through precancerous lesions to advanced cancer. Because DNA damage response (DDR) has been described as 1 of the first phases in genomic instability, we investigated the level of DDR activation and the apoptosis pathway in serous tubal intraepithelial carcinoma (STIC), the potential precursor of HGSC.
  
  
  METHODS
  A tissue microarray including 21 benign fallopian tubes, 21 STICs, 17 HGSCs from patients with STICs (associated ovarian cancer [AOC]) from the same individuals, and 30 HGSCs without STICs (non-AOC) was used in this study.Immunohistochemistry was performed to evaluate the level of DDR proteins (pATM, pChk2, γH2AX, 53BP1, and TRF2), apoptosis proteins (Bcl2, BAX, and BIM), and cyclin E.
  
  
  RESULTS
  The expression of all DDR proteins increased from benign fallopian tubes to STICs. The level of expression of pATM, pChk2, γH2AX, and TRF2 was also increased in STICs in comparison with AOC. BAX, BIM, and cyclin E expressions were high in STICs, whereas Bcl2 expression was low. Immunohistochemical profiles of AOC and non-AOC were also different.
  
  
  CONCLUSIONS
  These results suggest an activation of the DDR and apoptosis pathways in STICs, indicating that genomic instability may occur early in the precancerous lesions of HGSC.
authors.affiliation: *Centre de Recherche du Centre hospitalier de l'Université de Montréal; †Institut du Cancer de Montréal, Montreal, Quebec, Canada; ‡Department of Gynecology, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; Departments of §Pathology, and ∥Gynecology, Centre hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Gautier
authors.initials: G
authors.lastname: Chene
authors.forename: Veronique
authors.initials: V
authors.lastname: Ouellet
authors.forename: Kurosh
authors.initials: K
authors.lastname: Rahimi
authors.forename: Veronique
authors.initials: V
authors.lastname: Barres
authors.forename: Katia
authors.initials: K
authors.lastname: Caceres
authors.forename: Liliane
authors.initials: L
authors.lastname: Meunier
authors.forename: Louis
authors.initials: L
authors.lastname: Cyr
authors.forename: Manon
authors.initials: M
authors.lastname: De Ladurantaye
authors.forename: Diane
authors.initials: D
authors.lastname: Provencher
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Mes Masson
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018284:Cystadenocarcinoma, Serous / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000378:metabolism*; D005185:Fallopian Tube Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D011379:Prognosis; D015398:Signal Transduction; D046888:Tissue Array Analysis
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D045643:DNA Repair Enzymes