|Researchers Discover Molecular Differences between Low-Grade
and High-Grade Ovarian Cancers
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, appears 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
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
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 over-express 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
“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.
For more information about cancer, visit the NCI Web site at http://www.cancer.gov or
call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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