August 9, 2011 — A new genetic mutation that increases the risk for ovarian cancer has been discovered by a team of researchers in the United Kingdom; it was reported online August 7 in Nature Genetics.
In the general population, ovarian cancer affects about 1 in 70 women by the time they reach 80 years of age.
The presence of the newly discovered RAD51D gene mutation in a woman increases this risk to 1 in 11.
This is slightly lower than the increase in risk conferred by the BRCA mutations, which were discovered in the 1990s. A women carrying the BRCA1 mutation had a 5 in 10 chance of developing ovarian cancer, and a woman with a BRCA2 mutation has a 2 in 10 chance.
The BRCA mutations also increase the risk for breast cancer, but the new RAD51D mutation is not significantly linked to an increased risk for breast cancer; it appears to increase only the risk for ovarian cancer. In addition, it was identified in women who tested negative for BRCA mutations.
The discovery of the BRCA mutations led to genetic tests and counseling, with discussions about potential interventions including oophorectomy. This new discovery is likely to follow a similar path.
The British researchers estimate that a test for the RAD51D mutation will be available "within a few years."
"Women with a fault in the RAD51D gene have a 1 in 11 chance of developing ovarian cancer. At this level of risk, women may wish to consider having their ovaries removed after having children, to prevent ovarian cancer occurring," said senior author Nazneen Rahman, PhD, head of genetics and epidemiology at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
"There is also real hope on the horizon that drugs specifically targeted to the gene will be available," Dr. Rahman said in a statement. In addition to identifying the gene mutation, her team reported laboratory research showing that cells with a RAD51D mutation are highly sensitive to treatment with a PARP inhibitor — 90% of these cells died after exposure to the drug, compared with only 10% of cells with fully functioning RAD51D. However, this laboratory finding needs to be tested in clinical trials, the researchers emphasize.
PARP inhibitors, such as iniparib and olaparib, were designed to target cancers caused by faults in the BRCA1 and BRCA2 genes, and have already shown some promise in the treatment of ovarian and breast cancer. However, some recent results in breast cancer were disappointing, and no PARP inhibitor has yet reached the market.
Solid Evidence
"This is a very interesting report and provides solid evidence for another gene responsible for an increased genetic risk for ovarian cancer," said Maurie Markman, MD, professor of gynecologic oncology at the University of Texas M.D. Anderson Cancer Center, in Houston.
"The incidence of this genetic abnormality in the general population appears to be lower than that of BRCA1 and BRCA2, and the overall risk for ovarian cancer is not as great as reported for these previously recognized abnormalities. However, the proposed reason this genetic defect appears to increase ovarian cancer risk (impaired DNA repair) is similar to that of BRCA1 and BRCA2," he told Medscape Medical News.
"The preclinical studies suggesting a favorable impact of PARP inhibition suggest women with advanced or recurrent ovarian cancer who possess this genetic abnormality may experience clinical benefit following the administration of this novel class of antineoplastic agents," Dr. Markman explained. "It will be important for other investigative groups to confirm these interesting findings."
Some Families at High Risk
For their study, the British researchers identified 911 cases from breast–ovarian cancer families, and compared them with 1060 control subjects. The breast–cancer ovarian families had at least 1 case of breast cancer and at least 1 case of ovarian cancer, all of which were negative for BRCA1 and BRCA2 mutations.
The team found 8 women with the RAD51D gene mutation from among the 911 cases, and only 1 from among the 1060 control subjects (P = .001).
However, the mutations were not equally distributed in the series, the researchers note. There was a higher prevalence in families with more than 1 case of ovarian cancer, they report. Four mutations were found in 235 families with 2 or more cases of ovarian cancer (P = .005), and 3 mutations were detected in 59 families with 3 or more cases of ovarian cancer (P = .0005).
The researchers also tested for the mutation in samples from 13 relatives in the extended families of those with more than 1 case of ovarian cancer. "This revealed that 5 of 5 individuals affected with ovarian or breast cancer carried the family mutation, whereas 6 of the 8 unaffected relatives did not carry the family mutation."
"Several other cancers were present in relatives, such as pancreatic, prostate, and colorectal cancer," the researchers add. "However, the mutation status of these individuals is not known and additional studies will be required to evaluate whether RAD51D mutations predispose to other cancers."
The study was funded by Cancer Research UK. The researchers have disclosed no relevant financial relationships. Dr. Markman reports receiving grants from Eli Lilly, and serving as an advisor or consultant for Genentech, Celgene, Tibotec, and Boehringer Ingelheim.
Nat Genet. Published online August 7, 2011. Abstract
In the general population, ovarian cancer affects about 1 in 70 women by the time they reach 80 years of age.
The presence of the newly discovered RAD51D gene mutation in a woman increases this risk to 1 in 11.
This is slightly lower than the increase in risk conferred by the BRCA mutations, which were discovered in the 1990s. A women carrying the BRCA1 mutation had a 5 in 10 chance of developing ovarian cancer, and a woman with a BRCA2 mutation has a 2 in 10 chance.
The BRCA mutations also increase the risk for breast cancer, but the new RAD51D mutation is not significantly linked to an increased risk for breast cancer; it appears to increase only the risk for ovarian cancer. In addition, it was identified in women who tested negative for BRCA mutations.
The discovery of the BRCA mutations led to genetic tests and counseling, with discussions about potential interventions including oophorectomy. This new discovery is likely to follow a similar path.
The British researchers estimate that a test for the RAD51D mutation will be available "within a few years."
"Women with a fault in the RAD51D gene have a 1 in 11 chance of developing ovarian cancer. At this level of risk, women may wish to consider having their ovaries removed after having children, to prevent ovarian cancer occurring," said senior author Nazneen Rahman, PhD, head of genetics and epidemiology at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
"There is also real hope on the horizon that drugs specifically targeted to the gene will be available," Dr. Rahman said in a statement. In addition to identifying the gene mutation, her team reported laboratory research showing that cells with a RAD51D mutation are highly sensitive to treatment with a PARP inhibitor — 90% of these cells died after exposure to the drug, compared with only 10% of cells with fully functioning RAD51D. However, this laboratory finding needs to be tested in clinical trials, the researchers emphasize.
PARP inhibitors, such as iniparib and olaparib, were designed to target cancers caused by faults in the BRCA1 and BRCA2 genes, and have already shown some promise in the treatment of ovarian and breast cancer. However, some recent results in breast cancer were disappointing, and no PARP inhibitor has yet reached the market.
Solid Evidence
"This is a very interesting report and provides solid evidence for another gene responsible for an increased genetic risk for ovarian cancer," said Maurie Markman, MD, professor of gynecologic oncology at the University of Texas M.D. Anderson Cancer Center, in Houston.
"The incidence of this genetic abnormality in the general population appears to be lower than that of BRCA1 and BRCA2, and the overall risk for ovarian cancer is not as great as reported for these previously recognized abnormalities. However, the proposed reason this genetic defect appears to increase ovarian cancer risk (impaired DNA repair) is similar to that of BRCA1 and BRCA2," he told Medscape Medical News.
"The preclinical studies suggesting a favorable impact of PARP inhibition suggest women with advanced or recurrent ovarian cancer who possess this genetic abnormality may experience clinical benefit following the administration of this novel class of antineoplastic agents," Dr. Markman explained. "It will be important for other investigative groups to confirm these interesting findings."
Some Families at High Risk
For their study, the British researchers identified 911 cases from breast–ovarian cancer families, and compared them with 1060 control subjects. The breast–cancer ovarian families had at least 1 case of breast cancer and at least 1 case of ovarian cancer, all of which were negative for BRCA1 and BRCA2 mutations.
The team found 8 women with the RAD51D gene mutation from among the 911 cases, and only 1 from among the 1060 control subjects (P = .001).
However, the mutations were not equally distributed in the series, the researchers note. There was a higher prevalence in families with more than 1 case of ovarian cancer, they report. Four mutations were found in 235 families with 2 or more cases of ovarian cancer (P = .005), and 3 mutations were detected in 59 families with 3 or more cases of ovarian cancer (P = .0005).
The researchers also tested for the mutation in samples from 13 relatives in the extended families of those with more than 1 case of ovarian cancer. "This revealed that 5 of 5 individuals affected with ovarian or breast cancer carried the family mutation, whereas 6 of the 8 unaffected relatives did not carry the family mutation."
"Several other cancers were present in relatives, such as pancreatic, prostate, and colorectal cancer," the researchers add. "However, the mutation status of these individuals is not known and additional studies will be required to evaluate whether RAD51D mutations predispose to other cancers."
The study was funded by Cancer Research UK. The researchers have disclosed no relevant financial relationships. Dr. Markman reports receiving grants from Eli Lilly, and serving as an advisor or consultant for Genentech, Celgene, Tibotec, and Boehringer Ingelheim.
Nat Genet. Published online August 7, 2011. Abstract
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