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Team IDs Genetic Variant Associated With Breast Cancer Chemo Resistance

NEW YORK (GenomeWeb News) – A genetic variation in a gene coding for an enzyme called manganese superoxide dismutase can influence breast cancer patients' chemotherapy response, according to a new paper in the journal Clinical Cancer Research.

Researchers at the National Cancer Institute led the team, which genotyped nearly 600 American and Norwegian breast cancer patients to determine whether they carried an SOD2 variant suspected of influencing breast cancer risk and/or outcomes. Some of these women received chemotherapy as part of their treatment while others did not. The results suggest that the SOD2 variant tested is associated with treatment outcomes for breast cancer patients being treated with a drug called cyclophosphamide.

"This study shows how, with the progress of individualized medicine, a diagnostic test may be developed that determines whether a patient has certain genetic variations that may modify the effect of certain chemotherapies," lead author Sharon Glynn, a researcher at NCI's Laboratory of Human Carcinogenesis, said in a statement.

The manganese superoxide dismutase gene SOD2 codes for a mitochondrial enzyme that protects cells from oxidative damage by reactive oxygen species and environmental sources — including some chemotherapy drugs. Without such protective mechanisms, oxidation may lead to DNA damage, mutation, and tumor progression. In addition, the authors noted, once cells become used to such oxidative stress, they may become less susceptible to chemotherapy or radiotherapy.

A variation in SOD2 called Val16Ala — which involves a valine to alanine substitution — has been previously shown to affect the localization and activity of manganese superoxide dismutase. The Val16Ala variant also appears to be some 30 percent to 40 percent more enzymatically active than the Val form of the enzyme.

To determine what effect, if any, the Val16Ala variant had on breast cancer patient outcomes, Glynn and her colleagues genotyped 248 American and 340 Norwegian breast cancer patients. In the US, researchers used a TaqMan assay to genotype fresh-frozen breast tissue samples, and in Norway the genotyping was done using an Applied Biosystems 7900HT Fast Real-Time PCR System.

While SOD2 genotype was not associated with disease outcome in women who did not receive chemotherapy, the researchers did find a significant association between SOD2 genotype and breast cancer survival in individuals receiving chemotherapy — particularly when their treatment involved a drug called cyclophosphamide.

"[W]e found Val16Ala to be predictive of a long-term outcome among patients receiving chemotherapy, but not among untreated individuals," the authors noted. "Importantly, the effect of Val16Ala on outcome was largely restricted to patients treated with cyclophosphamide-containing regimens."

The team speculated that the variant, which results in a more active form of SOD2, may make breast cancer cells resistant to the chemotherapy by detoxifying the drug before it can kill cancer cells. Although they noted that more research will be needed to confirm the results and unravel the biology behind this finding, the researchers expressed enthusiasm about applying their finding down the road.

"In the future, such tests may be used to guide the treatment of patients with the SOD2 variation, ensuring that they receive a therapy that is more effective than cyclophosphamide-based therapies," senior author Stefan Ambs, a researcher at NCI's Laboratory of Human Carcinogenesis, said in a statement.

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