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�Because BRCA1 and BRCA2 have similar functions in terms of DNA repair,
we may be able to generalize these findings for women with either
mutation,� said Taniguchi, an assistant member of the Hutchinson
Center�s Human Biology and Public Health Sciences divisions.
BRCA2 works to repair damaged DNA; inherited mutations in this gene
disrupt that ability, which increases the risk of ovarian and breast
cancer. At the same time, such mutations also make cancer cells more
vulnerable to DNA-damaging agents such as cisplatin and carboplatin.
While ovarian tumors initially respond very well to platinum-based
chemotherapy, eventually between 70 percent and 80 percent of
advanced-stage ovarian-cancer patients develop a resistance to these
drugs.
�The majority of advanced-stage ovarian-cancer patients die due to
acquired resistance to platinum-based drugs. It is a serious problem,�
he said.
Taniguchi and colleagues at the Hutchinson Center, University of
Washington, Cedars-Sinai Medical Center and the Mayo Clinic have
uncovered how such resistance occurs. They found that when exposed to
cisplatin, some ovarian-cancer cells develop secondary mutations on
their BRCA2 gene that restore the gene�s ability to repair DNA. This
restoration of gene function then makes the cancer cells resistant to
chemotherapy.
�This event is unlike any previous mechanism of resistance to
chemotherapy identified in cancers,� said co-author Elizabeth Swisher,
M.D., associate professor of medicine in the Department of Obstetrics
and Gynecology and director of the Breast and Ovarian Cancer
Prevention Program at the University of Washington. �By identifying
the cause of chemotherapy resistance in these cancers, we may be able
to better predict who will respond to different chemotherapy agents
and find novel ways to re-sensitize tumors to chemotherapy that
otherwise would not have had a good response to treatment.�
If women with recurrent ovarian cancer are found to have a secondary
mutation on their BRCA2 gene, their cancer likely would be resistant
not only to platinum-based compounds but also other drugs such as PARP
inhibitors. �Testing whether relapsed tumors have a secondary mutation
of BRCA2 may be important to predict clinical outcome,� Taniguchi said.
The researchers suspect they may be able to generalize their findings
regarding secondary mutations in BRCA2 to other DNA-repair genes, such
as BRCA1, which may help explain drug resistance to a variety of
cancers, including those of the breast, prostate and pancreas.
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