Photo by Peter Barta
New research has revealed inherited genetic variations associated with rapid hearing loss in young cancer patients who receive cisplatin.
The drug is used to treat a range of cancers and is known to pose a risk of severe hearing loss, but the risk factors involved are not completely understood.
Now, researchers have found that variations in the gene ACYP2 are associated with an increased risk of cisplatin-related hearing loss.
Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported this discovery in Nature Genetics.
The researchers checked the DNA of 238 young patients with brain tumors for more than 1.7 million common genetic variations. The team found that variations in ACYP2 were associated with as much as a 4-fold greater risk of cisplatin-related hearing loss.
The screening is among the first to survey the genetic landscape for clues to help explain why the risk of cisplatin-related hearing loss varies so widely among patients.
“This is an important first step in being able to pinpoint patients who are at higher risk of developing cisplatin toxicity and to learn how to better manage that risk,” said study author Clinton Stewart, PharmD, also of St Jude.
The researchers confirmed the association between the high-risk ACYP2 variants and cisplatin-related hearing loss in a separate group of 68 brain tumor patients. The association was independent of other risk factors for cisplatin-related hearing loss, including patient age and receipt of radiation therapy.
Twenty-four of the 306 patients in this study had at least one copy of the high-risk ACYP2 variant. All 24 patients had measurable hearing loss that occurred as early as weeks after beginning cisplatin therapy.
Overall, however, the ACYP2 variant explained a relatively small proportion of hearing damage. Just 12.4% 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,” Dr Yang said. “Further research is needed to understand how the ACYP2 variations modify the risk . . . of cisplatin toxicity.”
Such studies could potentially lead to new medications to protect high-risk patients from cisplatin-related toxicity or help identify candidates for intensive monitoring of their hearing, Dr Stewart said. Early intervention could then be offered if problems are identified.
This study included patients enrolled in 1 of 3 trials designed by St Jude investigators for newly diagnosed pediatric brain tumors. The protocols involved similar treatment, including surgery to remove as much of the tumor as possible, followed by radiation, which was modified based on patient age and other risk factors.
The patients were scheduled to receive 4 rounds of cisplatin therapy. Patients’ hearing was tested before treatment began, after radiation therapy, after each round of chemotherapy, and then at regular standardized intervals. Analysis of the resulting data led to identification of ACYP2 and other variants.
“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,” said Giles Robinson, MD, also of St Jude.
“Hearing loss can have a significant impact on a child’s quality of life, language development, and academic performance. There is no easy fix, but the more we know about the risk factors, the better we will understand how to use cisplatin.”
