Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer.
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.
Pejovic
Tanja
T
Department of Obstetrics and Gynecology, Center for Women's Health, Oregon Health & Science University Cancer Institute, Portland, OR 97239, USA. pejovict@ohsu.edu
Yates
Jane E
JE
Liu
Hong Y
HY
Hays
Laura E
LE
Akkari
Yassmine
Y
Torimaru
Yumi
Y
Keeble
Winifred
W
Rathbun
R Keaney
RK
Rodgers
William H
WH
Bale
Allen E
AE
Ameziane
Najim
N
Zwaan
C Michael
CM
Errami
Abdellatif
A
Thuillier
Philippe
P
Cappuccini
Fabio
F
Olson
Susan B
SB
Cain
Joanna M
JM
Bagby
Grover C
GC
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
D018076:DNA, Complementary; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D012333:RNA, Messenger; D016685:Mitomycin