MEMORANDUM FOR: Science Writers and Editors on the Journal Press List

Inactivation of the BRCA1 Gene May Play a Role in Nonhereditary Breast and Ovarian Cancers

March 30, 2000 (EMBARGOED FOR RELEASE 4 P.M. EST April 4)

Katherine Arnold, Deputy News Editor, Dan Eckstein, (301) 986-1891, ext. 112

New research shows that inactivation of the BRCA1 gene by hypermethylation may be involved in development of some cases of primary breast and ovarian cancers.

Mutation of the BRCA1 gene is often involved in hereditary cases of breast and ovarian cancers, but extensive research has not found BRCA1 to be mutated in any cases of sporadic (nonhereditary) breast cancer and in few cases of sporadic ovarian cancer. Therefore, Manel Esteller, M.D., Ph.D., and James Herman, M.D., at The Johns Hopkins Oncology Center, Baltimore, Md., and colleagues looked for potential inactivation of BRCA1 by hypermethylation in breast and ovarian cancer tissues. Their results appear in the April 5 issue of the Journal of the National Cancer Institute.

Hypermethylation in tumor suppressor genes has been linked to their loss of expression. Methylation patterns in the BRCA1 promoter (sequences regulating gene expression) region were assessed in 21 breast cancer cell lines, human breast cancers grown in mice (xenografts), and 215 primary breast and ovarian carcinomas. A second series of ductal breast cancers and ovarian cancers were analyzed for loss of heterozygosity (LOH—meaning loss of one copy) of the BRCA1 gene.

The BRCA1 promoter was found to be unmethylated in all normal tissues and cancer cell lines tested. However, BRCA1 promoter hypermethylation was present in two breast cancer xenografts and in 11 (13%) of 84 unselected primary breast carcinomas. BRCA1 methylation was strikingly associated with the medullary (67% methylated; P = .0002 versus ductal) and mucinous (55% methylated; P = .0033 versus ductal) subtypes of breast cancer, which are overrepresented in BRCA1 families. In a second series of 66 ductal breast tumors informative for LOH, nine (20%) of 45 tumors with LOH had BRCA1 hypermethylation, while one (5%) of 21 without LOH was methylated (P = .15). In ovarian neoplasms, BRCA1 methylation was found only in tumors with LOH, four (31%) of 13 versus none of 18 without LOH (P = .02). The BRCA1 promoter was unmethylated in other tumor types.

The authors conclude that silencing of the BRCA1 gene by promoter hypermethylation occurs in primary breast and ovarian carcinomas, especially in the presence of LOH and in specific tissue subgroups. They add that these findings support a role for alteration of this tumor suppressor gene in development of sporadic breast and ovarian cancers.

Editorial writer Eric Fearon, M.D., Ph.D., University of Michigan Medical Center, Ann Arbor, says that the conclusions by Esteller et al. regarding a cause–effect relationship between BRCA1 promoter hypermethylation and inactivation may ultimately be well established. He notes that epigenetic mechanisms of gene inactivation, such as promoter hypermethylation, are undoubtedly important in cancer development and represent an alternative means of inactivating tumor suppressor genes. However, he adds that the standard of proof should be set quite high for establishing that hypermethylation of the promoter of any gene plays a critical role in loss of gene expression and cancer development. Because several transcription factors that specifically repress tumor suppressor gene expression have been identified, Dr. Fearon says it is worth bearing in mind that, in some cases, promoter hypermethylation may be a reflection rather than a cause of gene inactivation in cancer.

Contact: Vanessa Wasta, The Johns Hopkins Medical Center, (410) 616-2916; fax: (410) 614-2611. Editorial, Dr. Eric Fearon, (734) 764-1549; fax: (734) 647-7979.

Note: This memo to reporters is from the Journal staff and is not an official release of the National Cancer Institute (NCI) or Oxford University Press (OUP) nor does it reflect NCI or OUP policy. In addition, unless otherwise stated, all articles and items published in the Journal reflect the individual views of the authors and not necessarily the official points of view held by NCI, any other component of the U.S. government, OUP, or the organizations with which the authors are affiliated. Neither NCI nor any other component of the U.S. government nor OUP assumes any responsibility for the completeness of the articles or other items or the accuracy of the conclusions reached therein.



             
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