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Methylation Profiles of Sporadic Ovarian Tumors and nonmalignant Ovaries from High-Risk Women¹

Hamon Center for Therapeutic Oncology Research [A. R., A. K. V., J. O. S., K. J. E., R. M., J. D. H., L. G., A. F. G.], and Departments of Pathology [A. K. V., A. F. G.] and Obstetrics and Gynecology [J. O. S., K. J. E.], University of Texas Southwestern Medical Center, Dallas, Texas 85930; Laboratory of Gynecologic Oncology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115 [S. C. M.]; and Department of Obstetrics and Gynecology, Northwestern University Hospital, Chicago, Illinois 60611[D. A. F.]

Purpose: The purpose of this research was to examine the DNA methylation profiles of primary sporadic ovarian cancers and ovarian tissues from high-risk women.

Experimental Design: We analyzed the DNA methylation status of nine cancer-related genes in 49 primary ovarian tumors, 39 nonmalignant ovarian tissues obtained from 16 women with no known risk and from 23 high-risk women with a strong family history of breast and/or ovarian cancer or BRCA1 germ-line mutations, and 11 ovarian cancer cell lines, by methylation-specific PCR.

Results: Our findings are as follows: (a) methylation rates of four of nine genes, RASSF1A (41%), HIC1 (35%), E-cadherin (29%), and APC (18%) were significantly higher in tumors compared with controls. At least one of the four genes was methylated in 76% of the tumors; (b) a low frequency of methylation was present in nonmalignant tissues; (c) no significant differences in methylation frequencies were seen between the nonmalignant ovarian tissues from women at high-risk and those with no known risk of developing ovarian cancer; (d) methylation of the BRCA1 gene was found in 10% of sporadic tumors but in none of the samples from women with a germ-line BRCA1 mutation; and (e) ovarian cancer cell lines showed a similar frequency of methylation to ovarian tumors except for the HIC1 gene.

Conclusions: Our results suggest that aberrant methylation of specific genes, including two not described previously, may be important in ovarian cancer pathogenesis but not in ovaries at risk for cancer development.

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