Genetic Variant Associated with Resistance to Chemotherapy Drug in Women with Breast Cancer
News Jun 10, 2009
Researchers have found links between an individual's genetics and their response to treatment with chemotherapy. The findings, by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, and colleagues, show how a genetic variant, located in the SOD2 gene, may affect how a person responds to the chemotherapy drug cyclophosphamide. Cyclophosphamide is used in the treatment of breast and other cancers.
The SOD2 gene produces a key protein that protects cells from damage by molecules known as reactive oxygen species, or free radicals. Reactive oxygen species are produced by normal cellular processes and the action of some chemotherapy drugs.
The findings represent the first preliminary evidence pointing toward a mechanism and a potential biomarker for cyclophosphamide resistance in breast cancer patients. The study appeared online June 9, 2009, in Clinical Cancer Research.
"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," said study author Sharon Glynn, Ph.D., of NCI's Center for Cancer Research.
"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," added senior author Stefan Ambs, Ph.D., also of the Center for Cancer Research.
Most genes in human cells are present in two copies-one inherited from the mother and the other inherited from the father. These gene copies can vary from one another. Some variations in genes play an important role in how a gene is expressed or how its protein product functions.
The variant identified by the researchers in the SOD2 gene affects both the structure and the function of the encoded protein, an enzyme known as manganese superoxide dismutase (MnSOD) and affects the ability of MnSOD to reach its proper location in the cell and its activity level.
MnSOD normally functions inside cellular compartments known as mitochondria and helps protect cells from damage caused by reactive oxygen species formed during cellular metabolism. Excessive levels of reactive oxygen species can be toxic to cells. Indeed, some anticancer drugs depend on increased production of reactive oxygen species to kill cancer cells.
The research team says more work is necessary to confirm these findings and to examine the precise mechanism by which a genotype influences the response of cancer cells to cyclophosphamide. The team plans to examine the influence of several variations on the resistance to other chemotherapies.
Molecular biologists long thought that domains in the genome’s 3D organization control how genes are expressed. After studying highly rearranged chromosomes in fruit flies, researchers now reveal that while this is the case for some genes, their results challenge the generality of this for many others.READ MORE