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Cytogenetic Instability in Ovarian Epithelial Cells from Women at Risk of Ovarian Cancer

¹ Department of Obstetrics and Gynecology, ² Center for Women's Health, ³ Oregon Health & Science University Cancer Institute, and ⁴ Department of Medicine and Molecular and Medical Genetics, Oregon Health & Science University; ⁵ Northwest Veterans Affairs Cancer Research Center, Portland Veterans Affairs Medical Center, Portland, Oregon; ⁶ Department of Pathology, University of Maryland, Baltimore, Maryland; ⁷ Department of Genetics, Yale University School of Medicine, New Haven, Connecticut; ⁸ Department of Clinical and Human Genetics, Vrije University Medical Center; ⁹ MRC-Holland B.V., Amsterdam, the Netherlands; and ¹⁰ Department of Pediatric Oncology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, the Netherlands

Requests for reprints: Tanja Pejovic, Department of Obstetrics and Gynecology, L-466, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Phone: 503-494-2056; Fax: 503-494-1835; E-mail: pejovict{at}ohsu.edu.

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. (Cancer Res 2006; 66(18): 9017-25)

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