title: Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer.
abstract: Fanconi anemia is an inherited cancer predisposition disease characterized by cytogenetic and cellular hypersensitivity to cross-linking agents. Seeking evidence of Fanconi anemia protein dysfunction in women at risk of ovarian cancer, we screened ovarian surface epithelial cells from 25 primary cultures established from 22 patients using cross-linker hypersensitivity assays. Samples were obtained from (a) women at high risk for ovarian cancer with histologically normal ovaries, (b) ovarian cancer patients, and (c) a control group with no family history of breast or ovarian cancer. In chromosomal breakage assays, all control cells were mitomycin C (MMC) resistant, but eight samples (five of the six high-risk and three of the eight ovarian cancer) were hypersensitive. Lymphocytes from all eight patients were MMC resistant. Only one of the eight patients had a BRCA1 germ-line mutation and none had BRCA2 mutations, but FANCD2 was reduced in five of the eight. Ectopic expression of normal FANCD2 cDNA increased FANCD2 protein and induced MMC resistance in both hypersensitive lines tested. No FANCD2 coding region or promoter mutations were found, and there was no genomic loss or promoter methylation in any Fanconi anemia genes. Therefore, in high-risk women with no BRCA1 or BRCA2 mutations, tissue-restricted hypersensitivity to cross-linking agents is a frequent finding, and chromosomal breakage responses to MMC may be a sensitive screening strategy because cytogenetic instability identified in this way antedates the onset of carcinoma. Inherited mutations that result in tissue-specific FANCD2 gene suppression may represent a cause of familial ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Center for Women's Health, Oregon Health & Science University Cancer Institute, Portland, OR 97239, USA. pejovict@ohsu.edu
authors.forename: Tanja
authors.initials: T
authors.lastname: Pejovic
authors.forename: Jane E
authors.initials: JE
authors.lastname: Yates
authors.forename: Hong Y
authors.initials: HY
authors.lastname: Liu
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hays
authors.forename: Yassmine
authors.initials: Y
authors.lastname: Akkari
authors.forename: Yumi
authors.initials: Y
authors.lastname: Torimaru
authors.forename: Winifred
authors.initials: W
authors.lastname: Keeble
authors.forename: R Keaney
authors.initials: RK
authors.lastname: Rathbun
authors.forename: William H
authors.initials: WH
authors.lastname: Rodgers
authors.forename: Allen E
authors.initials: AE
authors.lastname: Bale
authors.forename: Najim
authors.initials: N
authors.lastname: Ameziane
authors.forename: C Michael
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Errami
authors.forename: Philippe
authors.initials: P
authors.lastname: Thuillier
authors.forename: Fabio
authors.initials: F
authors.lastname: Cappuccini
authors.forename: Susan B
authors.initials: SB
authors.lastname: Olson
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Cain
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
mesh_terms: D000328:Adult; D000368:Aged; D019457:Chromosome Breakage; D019175:DNA Methylation; D018076:DNA, Complementary / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D016685:Mitomycin / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000473:pathology / Q000502:physiology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018076:DNA, Complementary; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D012333:RNA, Messenger; D016685:Mitomycin