A new study suggests that ovarian tumors classified as serous borderline or low malignant potential (LMP) are not early precursors in the development of aggressive ovarian cancer, but may instead be part of an entirely different class of tumors. Furthermore, genes that were identified in this study as being expressed, or active, in these different classes of tumors could help identify targets for more specific diagnostics and therapies to treat this disease.

LMP is different than serous high-grade ovarian tumors (more aggressive tumors) yet shares remarkable similarities with serous low-grade ovarian tumors (less aggressive tumors). Both serous high-grade and low-grade ovarian tumors are types of invasive ovarian cancer. Whether serous LMP tumors can give rise to invasive ovarian cancers has been controversial.

The results of this study, which was conducted by a research team that included scientists from the National Cancer Institute (NCI), part of the National Institutes of Health, the Dana-Farber Cancer Institute, Boston, Mass., and the M.D. Anderson Cancer Center, Houston, Texas, appear in the November 15, 2005, issue of Cancer Research*. The study was supported by a Specialized Program of Research Excellence (SPORE) grant from the NCI. The research teams from the Dana-Farber Cancer Institute and M.D. Anderson Cancer Center are SPORE grant recipients.

Using a gene expression technique that reveals which genes are turned on or off in a cell, the researchers identified distinct differences between the gene expression profiles of LMP tumors and high-grade ovarian malignancies. The gene expression results suggested that serous low-grade ovarian tumors are more similar to LMP tumors than to serous high-grade ovarian cancers and that different biochemical pathways may be involved in the development of LMP and low-grade tumors compared to high-grade tumors.

"Patients with serous low-grade or high-grade ovarian tumors currently receive the same treatment, which is surgery followed by chemotherapy. However, the finding that low-grade tumors are more similar to LMP tumors has significant therapeutic implications," said Michael Birrer, M.D., Ph.D., study leader and head, Molecular Mechanism Section at NCI. "Women with low-grade invasive tumors may benefit from therapies that are different from those given to patients with high-grade tumors. Furthermore, the biochemical pathways identified in this study may provide targets for more rational therapies for these different tumor types."

The most common type of ovarian cancer arises from the epithelial cells that line the surface of the ovary. Epithelial ovarian tumors, approximately 50 percent of which are classified as serous (the cells have glandular features), constitute 80 percent of all ovarian tumors. The classification of invasive serous ovarian tumors as either low-grade or high-grade is an indication of the clinical course of the disease, with high-grade tumors having the poorest prognosis. David M. Gershenson, M.D. a co-author from M.D. Anderson Cancer Center noted, "The classification of invasive serous ovarian tumors as either low-grade or high-grade is an indication of the clinical course of the disease with high-grade tumors having the poorer prognosis."

This study compared gene expression in ovarian tumors and normal epithelial cells. High-grade tumors over-expressed genes that control various cell functions related to the development of cancer. These genes included those that control cell growth or cause DNA instability, as well as genes that can silence the expression of other genes, information that may provide important clues about why certain tumors are more aggressive than others. In contrast, low-grade and LMP tumors did not overexpress these genes, and the gene expression profiles of LMP and low-grade tumors were similar. LMP tumors were characterized by the expression of growth control pathways, such as the p53 pathway in the cell. These findings suggest that distinct biological mechanisms may be involved in the initiation of LMP and high-grade tumors and that some LMP tumors may give rise to invasive low-grade tumors.

"This study analyzed over 40,000 genes that were expressed in these different ovarian tumor types. Using the gene expression profiles we can determine the relationship between these tumors," said Birrer.

The tumors analyzed in this study included a total of 80 primary ovarian tumors. Of these, 20 were LMP tumors, all of which were classified as grade 0 and half of which were classified as stage I. The remaining 60 tumors were invasive cancers. The majority of these were grade 3, stage III. Gene expression was also assessed in 10 samples of normal ovarian epithelial tissue.

"This study is unique because the cancer cells analyzed were obtained by microdissecting the tumor. This is a very precise method to obtain a pure sample of tumor cells," said Samuel Mok, Ph.D., associate professor, Harvard, and study collaborator. "The genes identified were expressed specifically in the ovarian cancer cell and may provide insights into how genes within cancer cells are modulating normal cells to support malignant tumor growth."

Among gynecologic malignancies, ovarian cancer has the highest rate of mortality in women in the United States with an estimated 22,220 new cases in 2005 and over 16,000 deaths.

* Bonome T, Lee J, Park D, Radonovich M, Pisemasison C, Gardner G, Hao K, Wong W, Barrett C, Lu K, Sood A, Gershenson D, Mok S, Birrer M. Expression profiling of serous low malignant potential, low-grade, and high-grade tumors of the ovary. Cancer Research November 15, 2005; Vol. 65, Issue 22.

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