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Genetic Studies Yield Clues to Treatment-Related Side Effects in Children with Cancer

February 26, 2015, by NCI Staff

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Researchers have identified genetic variations in children with brain cancer that are associated with hearing damage caused by the chemotherapy drug cisplatin. Children with these inherited variations who were treated with cisplatin had an increased risk of rapid hearing loss, the researchers reported in Nature Genetics.

Cisplatin is an important part of treatment for many children and adolescents with cancer. But in some patients the drug (and a related drug, carboplatin) causes hearing loss. It’s unclear, however, why the risk of cisplatin-related hearing loss varies widely among patients.

To study the possible role of genetic factors in predisposition to hearing loss, scientists at St. Jude Children’s Research Hospital tested 1.7 million genetic markers in DNA from 238 young patients with brain tumors. Variations in the gene ACYP2 were associated with cisplatin-related hearing loss, with one variant showing a particularly strong association, the researchers found.

All children in the study who carried this variant developed hearing loss, whereas just over half of the children who did not carry the variant did. Hearing loss in children with the variant was also more rapid and severe. The association with this risk variant was confirmed in a separate group of 68 young patients with brain tumors.

The discovery is an important first step in being able to identify patients who are at higher risk of developing treatment-related hearing loss and learning how to better manage that risk, the study authors said in a press release. Nevertheless, they cautioned, the ACYP2 variant explained a relatively small proportion of hearing damage. Just 12 percent of the 194 patients in this study with cisplatin-related hearing loss carried the ACYP2 variant.

“This suggests that other genes also contribute to the risk of hearing loss and are yet to be identified,” said co-author Jun J. Yang, Ph.D., in the release. Further research is needed to understand how the ACYP2 variations modify a patient’s risk of treatment-related side effects, Dr. Yang added.

Hearing loss can affect a child’s quality of life, language development, and academic performance. “Our primary goal is to cure children with brain tumors, but we also have a duty to help patients survive with a high quality of life,” noted co-author Giles Robinson, M.D. “There is no easy fix, but the more we know about the risk factors [for hearing loss], the better we will understand how to use cisplatin.”

In a separate study, another team from St. Jude found that genetic variation in the gene CEP72 is associated with peripheral neuropathy, a common side effect of vincristine, which is commonly used to treat children with acute lymphoblastic leukemia. Currently there are no reliable ways to identify patients at high risk of vincristine¬-induced neuropathy or strategies to reduce its severity.

William E. Evans, Pharm.D., of St. Jude and his colleagues reported their findings in JAMA on February 24.

If the results are confirmed, doctors could potentially identify individuals at risk, and researchers could explore alternative treatment strategies for these patients, the study authors noted.

The ability to assess risk would “allow for greater transparency in discussions of risk and benefits of therapy with patients and their family members,” wrote Howard L. McLeod, Pharm.D., of the Moffitt Cancer Center in an accompanying editorial in JAMA. The study “also represents an initial robust effort to generate predictors for adverse drug reactions in cancer care,” Dr. McLeod added.

More information on pediatric brain cancers is available on NCI’s Brain Tumor page.

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