Quantitative analysis of γ-H2AX and p53 nuclear expression levels in ovarian and fallopian tube epithelium from risk-reducing salpingo-oophorectomies in BRCA1 and BRCA2 mutation carriers

Int J Gynecol Pathol. 2014 May;33(3):309-16. doi: 10.1097/PGP.0b013e31829c673b.

Abstract

Mutations in BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Increased lifetime ovarian cancer risk among BRCA1/BRCA2 mutation carriers can be substantially decreased by risk-reducing salpingo-oophorectomy (RRSO), which also provides material for molecular research on early pathogenesis of serous ovarian cancer. RRSO studies have suggested fallopian tube as a primary site of serous high-grade ovarian cancer. In this study, the nuclear expression levels of γ-H2AX and p53 using immunohistochemical (IHC) study was quantitatively assessed in ovarian and fallopian tube epithelium derived from RRSOs in 29 BRCA1 and BRCA2 mutation carriers and in 1 patient with a strong family history of breast and ovarian cancer but showing an unknown BRCA status. Both p53 and γ-H2AX nuclear staining levels were significantly higher in BRCA1/2 mutation-positive fallopian tube epithelium compared with the control fallopian tube epithelium (P<0.006 and P=0.011, respectively). Nuclear expression levels of p53 and γ-H2AX were similar between the BRCA1/2 mutation-positive ovarian epithelium and controls. Both γ-H2AX and p53 showed significantly higher nuclear expression levels in BRCA1/2 mutation-positive fallopian tube epithelium compared with BRCA1/2 mutation-positive ovarian epithelium (P<0.0001 and P<0.0001, respectively). BRCA1/2 mutation-positive fallopian tube epithelium showed a positive correlation between the γ-H2AX and p53 nuclear expression levels (Pearson r=0.508, P=0.003). Our results of quantitative nuclear p53 and γ-H2AX expression levels in ovarian and fallopian tube epithelium derived from RRSO in high-risk patients support the previously suggested role of fallopian tube epithelium serving as a possible site of initial serous ovarian carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Carcinoma, Ovarian Epithelial
  • Cell Nucleus / metabolism
  • Cystadenocarcinoma, Serous / genetics*
  • Cystadenocarcinoma, Serous / pathology
  • Cystadenocarcinoma, Serous / prevention & control
  • Cystadenocarcinoma, Serous / surgery
  • Epithelium / pathology
  • Fallopian Tube Neoplasms / genetics*
  • Fallopian Tube Neoplasms / pathology
  • Fallopian Tube Neoplasms / prevention & control
  • Fallopian Tube Neoplasms / surgery
  • Fallopian Tubes / pathology*
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • Histones / metabolism*
  • Humans
  • Middle Aged
  • Mutation
  • Neoplasms, Glandular and Epithelial / genetics*
  • Neoplasms, Glandular and Epithelial / pathology
  • Neoplasms, Glandular and Epithelial / prevention & control
  • Neoplasms, Glandular and Epithelial / surgery
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / prevention & control
  • Ovarian Neoplasms / surgery
  • Ovariectomy
  • Ovary / pathology*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • H2AX protein, human
  • Histones
  • Tumor Suppressor Protein p53