title: 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.
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.
authors.affiliation: Laboratory of Cancer Biology (S.S., J.I.), Institute of Biomedical Technology, BioMediTech Medical School (J.M.), University of Tampere Department of Obstetrics and Gynecology (S.S., J.M.) Fimlab Laboratories (T.T.) Genetics Outpatient Clinic and Department of Dermatology (S.-L.S.), Tampere University Hospital, Tampere Department of Surgery (J.-P.M.), Jyväskylä Central Hospital, Jyväskylä School of Medicine, University of Eastern Finland (J.-P.M.), Kuopio, Finland.
authors.forename: Synnöve
authors.initials: S
authors.lastname: Staff
authors.forename: Teemu
authors.initials: T
authors.lastname: Tolonen
authors.forename: Satu-Leena
authors.initials: SL
authors.lastname: Laasanen
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Jorma
authors.initials: J
authors.lastname: Isola
authors.forename: Johanna
authors.initials: J
authors.lastname: Mäenpää
mesh_terms: D000328:Adult; D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D002467:Cell Nucleus / Q000378:metabolism; D018284:Cystadenocarcinoma, Serous / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control / Q000601:surgery; D004848:Epithelium / Q000473:pathology; D005185:Fallopian Tube Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control / Q000601:surgery; D005187:Fallopian Tubes / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control / Q000601:surgery; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control / Q000601:surgery; D010052:Ovariectomy; D010053:Ovary / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C468783:H2AX protein, human; D006657:Histones; D016159:Tumor Suppressor Protein p53