GENETICS OF HEARING LOSS AFTER PAEDIATRIC BRAIN TUMOUR TREATMENT

Using a genome-wide associated study approach, researchers have identified inherited genetic variations in the ACYP2gene that were linked to as much as a fourfold greater risk of rapid hearing loss in young patients with newly diagnosed brain tumors treated with cisplatin chemotherapy. The study findings may lead to new interventions to protect high-risk patients from cisplatin-related toxicity or help identify high-risk patients for intensive monitoring of their hearing. The study by Xu et al is published in Nature Genetics.

Study Methodology 

The study included patients enrolled in one of three clinical trials for newly diagnosed pediatric brain tumors designed by investigators at St. Jude Children’s Research Hospital. The protocols involved similar treatment, including surgery to remove as much of the tumor as possible, followed by radiation therapy, which was modified based on patient age and other risk factors.

The patients were scheduled to receive four rounds of cisplatin therapy. The patients’ hearing was tested at various intervals, including before the start of treatment, after radiation therapy, after each round of chemotherapy, and at regular standardized intervals.

Study Findings

The researchers analyzed the DNA of 238 children for more than 1.7 million common genetic variations and found that common variants in the ACYP2 gene were associated with a fourfold greater risk of rapid cisplatin-related hearing loss. The association between the high-risk ACYP2 variants and cisplatin-related hearing loss was confirmed in a separate group of 68 similarly treated children. The link was independent of other risk factors for cisplatin-related hearing loss, including patient age and radiation therapy.

Of the 306 patients in the study, 24 had at least one copy of the high-risk ACYP2 gene variant. All 24 patients had measurable hearing loss, which occurred as early as a few weeks after beginning cisplatin therapy.

However, overall, the researchers found that the ACYP2 variant explained a relatively small proportion of hearing damage. Just 12.4% of the 194 patients with cisplatin-related hearing loss carried the ACYP2 variant.

“This [finding] suggests that other genes also contribute to the risk of hearing loss and are yet to be identified,” said Jun J. Yang, PhD, an assistant member of the St. Jude Department of Pharmaceutical Sciences and a co-corresponding author of the study, in a statement. “Further research is needed to understand how the ACYP2 variations modify the risk of cisplatin toxicity facing patients."

The study results could potentially lead to new medications to protect high-risk patients from cisplatin-related toxicity or help identify patients for intensive monitoring of their hearing, said the researchers.

Dr. Yang and Clinton F. Stewart, PharmD, of St. Jude’s Children’s Research Hospital, are the corresponding authors for the Nature Genetics article.

Funding for the study was provided by the National Institutes of Health and the American Lebanese Syrian Associated Charities (ALSAC).