July 2002

From Journal of the National Cancer Institute

Similar pathways may be involved in hereditary and sporadic ovarian cancers

New research suggests that BRCA1 and BRCA2 gene mutations lead to hereditary ovarian cancers through different pathways, but that these pathways may be similar to ones at work in sporadic ovarian cancers. These findings appear in the July 3 issue of the Journal of the National Cancer Institute.

BRCA1 and BRCA2 are tumor suppressor genes that play important roles in cellular functioning such as DNA damage repair. Mutations in these genes have been associated with 5% to 10% of epithelial ovarian cancers. Whether BRCA1 and BRCA2 mutations lead to cancer through similar or different pathways is unclear. A past study of BRCA1 and BRCA2-linked breast cancers revealed distinct differences in gene expression patterns between the two types of mutations.

To determine whether genetic differences also exist in BRCA-linked ovarian cancers, Amir A. Jazaeri, M.D., and Edison T. Liu, M.D., of the National Cancer Institute and their colleagues compared gene expression patterns of tumors from 18 ovarian cancer patients with BRCA1 mutations, 16 patients with BRCA2 mutations, and 27 patients with sporadic ovarian cancers.

The authors found that overall patterns of gene expression differed between the BRCA1-associated and BRCA2-associated tumors. Of the roughly 6,500 genes analyzed, 110 were found to be different between BRCA1- and BRCA2-associated tumors. However, the authors discovered that the same genes whose expression separated BRCA1-associated and BRCA2-associated tumors also identified two major groups of sporadic cancers.

"The observation that BRCA-associated gene expression profiles are recapitulated in major subsets of sporadic tumors suggests that molecular mechanisms common to both hereditary and sporadic ovarian carcinogenesis exist," the authors conclude.

In an accompanying editorial, Ingrid A. Hedenfalk, Ph.D., of the National Human Genome Research Institute at the National Institutes of Health, says a possible explanation for this finding might be the disruption of BRCA function in sporadic tumors, either of the BRCA genes themselves, or of other key molecules in the same functional pathways. Other possible explanations include differences in tumor progression and cellular origin between BRCA1 and BRCA2 ovarian cancers that are shared by sporadic cancers, she says.

"Increased knowledge of changes in gene expression in ovarian carcinogenesis may lead to improvements in detection and therapeutic strategies, potentially improving the management of ovarian cancer patients," Hedenfalk concludes.

Contact: Daniel Lum, Genome Institute of Singapore, (65) 6827 5275; fax: (65) 6827 5201, gislumd@nus.edu.sg

Editorial: Geoff Spencer, National Human Genome Research Institute, (301) 402-0911; fax: 301-402-2218, spencerg@mail.nih.gov

Jazaeri A, Yee C, Sotiriou C, Brantley K, Boyd J, Liu E. Gene expression profiles of BRCA1-linked, and sporadic ovarian cancers? J Natl Cancer Inst 2002;94:990--1000.

Hedenfalk I. Gene expression profiling of hereditary and sporadic ovarian cancers reveals unique BRCA1 and BRCA2 signatures. J Natl Cancer Inst 2002;94:960--1.

Attribution to the Journal of the National Cancer Institute is requested in all news coverage.











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