The study, which implicates the genes EPHA5, ARHGEF10, and PRX, is the first to mine large swaths of the human genome for predictors of chemotherapy side effects. Further research into these genes and others may enable clinicians to use genomic information to more safely deliver these potentially toxic treatments.
"Our study creates a path for how to approach the whole genome in order to tailor cancer treatments," saysAndreas Beutler, M.D., an oncologist at Mayo Clinic Cancer Center and senior author of the study. "That is important because we not only want to cure people's cancer or help them live longer, but we also want to provide them with the best quality of life."
Chemotherapy-induced peripheral neuropathy affects an estimated 30 to 40 percent of cancer patients treated with chemotherapy agents. The symptoms can be as mild as a light tingling or numbness, but can progress to a loss of feeling in the hands and feet, or to the point where patients can no longer walk normally and are left with a permanent feeling of numbness or pain. Currently, there is no way to predict which patients undergoing chemotherapy will develop this side effect or to what degree.
There are approximately 50 genes linked to a hereditary form of peripheral neuropathy. However, many of the people who have one of these genes experience no symptoms until they are exposed to chemotherapy. Dr. Beutler decided to first consider those 50 genes as the most likely suspects, and then expand his search to the wider human genome for other predictors of chemotherapy-induced peripheral neuropathy.
Dr. Beutler's approach relied on exome sequencing, a type of DNA sequencing that focuses on the exonic regions of the genome that code for functional proteins. These protein-coding regions are believed to harbor about 85 percent of all disease-causing mutations.
Dr. Beutler and his colleagues performed exome sequencing on 20,794 genes from 119 cancer patients, over half of whom had developed chemotherapy-induced peripheral neuropathy during the course of a chemotherapy clinical trial.
First, they looked at the 50 hereditary neuropathy genes and found one - EPHA5 - that appeared to predispose the patients to chemotherapy-induced peripheral neuropathy. Next, researchers analyzed the remaining 20,000 genes and discovered two new genes - ARHGEF10 and PRX - that are also associated with chemotherapy-induced peripheral neuropathy. They validated those findings in another group of 75 cancer patients.
The results suggest that the two conditions, hereditary neuropathy and chemotherapy-induced peripheral neuropathy, may share genetic roots in some patients. They also point to ways that clinicians can improve cancer treatment. For instance, if clinicians know which patients are at risk for a particular chemotherapy side effect, they can use the information to individualize treatment.
Dr. Beutler and his team plan to expand their study to look at the entire genome, not just the protein-coding regions, in as many as 1,000 cancer patients. Dr. Beutler says any additional genes they find will add to the larger picture of symptom control in cancer treatment.
"What we are doing at Mayo is much larger than just uncovering a handful of genes," says Dr. Beutler. "We are using cutting-edge genomics research to enhance our strengths in clinical trials and develop new methods to individualize medicine."
Funding for the study was provided by the American Cancer Society, the National Institutes of Health grants CA124477 and CA37404, the Mayo Clinic Center for Individualized Medicine and the Richard M. Schulze Family Foundation.
About Mayo Clinic Cancer Center
As a leading institution funded by the National Cancer Institute, Mayo Clinic Cancer Center conducts basic, clinical and population science research, translating discoveries into improved methods for prevention, diagnosis, prognosis and therapy. For information on cancer clinical trials, call 507-538-7623.
About Mayo Clinic
Mayo Clinic is the first and largest integrated, not-for-profit group practice in the world. Doctors from every medical specialty work together to care for patients, joined by common systems and a philosophy of "the needs of the patient come first." More than 3,700 physicians, scientists and researchers, and 50,100 allied health staff work at Mayo Clinic, which has campuses in Rochester, Minn; Jacksonville, Fla; and Scottsdale/Phoenix, Ariz.; and community-based providers in more than 70 locations in southern Minnesota., western Wisconsin and northeast Iowa. These locations treat more than half a million people each year. To obtain the latest news releases from Mayo Clinic, go to www.mayoclinic.org/news. For information about research and education, visit www.mayo.edu. MayoClinic.com (www.mayoclinic.com)
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