Cisplatin-induced ototoxic effects in patients with testicular cancer are associated with a protein-coding variation in the transporter gene SLC16A5, according to an international group of researchers.
As Dr. Bruce C. Carleton told Reuters Health by email, "Hearing loss is a debilitating side effect from cisplatin that occurs in 20 to 40% of testicular-cancer patients treated with this drug. In this study, we identified a variant in the SLC16A5 gene that decreases the chance of experiencing hearing loss caused by cisplatin more than tenfold."
Dr. Carleton, of BC Children’s Hospital Research Institute in Vancouver, Canada, and colleagues studied data on 188 patients with a median age of 31 years. All had been treated with cisplatin-based chemotherapy. The discovery cohort consisted of 23 cases and 73 controls and the replication cohort of 14 cases and 78 controls.
Cisplatin-associated ototoxic effects were diagnosed by two audiologists and the patients were screened for more than 7,900 variants within the absorption, distribution, metabolism and excretion gene regions.
Association and fine-mapping analyses revealed a protein-coding variant of SLC16A5 that had a protective effect against cisplatin-induced ototoxic effects in both independent cohorts. The association remained significant after Bonferroni correction in the combined cohort (odds ratio, 0.06), the researchers report in JAMA Oncology, online April 27.
In vitro studies showed that SLC16A5-silencing altered cellular responses to cisplatin treatment, supporting its role in the development of cisplatin-induced ototoxic effects.
The researchers further note that SLC16A5 is inhibited by cimetidine. Its addition to cisplatin treatments in rat cochlear cultures and in mice prevented such ototoxic events without compromising cisplatin’s antitumor activity.
Given these results, continued Dr. Carleton, "Testing for this variant would aid in predicting which patients are more likely to experience hearing loss from cisplatin such that proper hearing screening can accompany cancer treatment."
"The findings from this study," he concluded, "also have important implications for the investigation of drugs that inhibit the SLC16A5 gene to potentially use as protective agents against the development of cisplatin-induced hearing loss."