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GWAS Unearths Loci Linked to Hearing Loss Risk After Cisplatin Chemotherapy

NEW YORK (GenomeWeb) – In Nature Genetics, an international team led by investigators at St. Jude Children's Research Hospital described variants in the ACYP2 gene that appear to notch up the risk of hearing loss in children treated with the anticancer drug cisplatin.

The researchers relied on a genome-wide association study that included 238 children diagnosed with embryonal brain tumors. By tracking hearing loss, or "ototoxicity," in the children over time as they received cisplatin therapy, they were able to compare genotype and treatment protocol patterns in those who developed hearing problems and those who didn't.

The search led to common variants in the enzyme-coding gene ACYP2 that were overrepresented in cisplatin-treated children who developed significant hearing loss — associations the team validated through testing on another 68 young children treated for brain tumors.

At least one of the ACYP2 variants appeared to coincide with hearing loss severity and rapidity, suggesting it could help in identifying some individuals at high risk of ototoxicity after cisplatin treatment.

"The clinical usefulness of these findings should be examined in future trials, particularly in the context of potential clinical interventions for at-risk patients," St. Jude pharmaceutical sciences researchers Jun Yang and Clinton Stewart, the study's senior authors, and their colleagues wrote. "GWAS with even greater sample sizes is also needed to characterize additional pharmacogenetic variants influencing cisplatin-related ototoxicity."

Physicians frequently turn to cisplatin for treating solid tumors, the team explained. But the drug's effectiveness often comes at a cost, with as many as 70 percent of cisplatin-treated children developing hearing loss, depending on the dose used.

Some of the factors that enhance this risk are known, such as young age or certain types of irradiation. Nevertheless, the variability in hearing loss risk among children receiving similar treatments suggests genetic contributors may be at play as well, prompting the researchers to pursue potential genetic contributors to this process.

The "[i]dentification of the genetic basis of cisplatin-related ototoxicity could lead to an improved understanding, advance protective interventions, and facilitate the development of less ototoxic therapies," they reasoned.

With that in mind, the team followed 238 children diagnosed with embryonal brain tumors. Of those, 61 percent of the children developed ototoxicity, usually within the first six months after their first cisplatin treatment. For 37 percent of the children, hearing loss was more pronounced and reached the "clinically relevant" level.

A look at array-based genotyping patterns in the children with or without ototoxicity over time led the team to one variant in the chromosome 2 gene ACYP2 that had genome-wide significant ties to hearing loss.

All of the children who carried the allele had hearing lost, though ototoxicity was present in more than half of the children who didn't — a pattern the researchers replicated through targeted gene resequencing and testing in another 68 cisplatin-treated children with brain cancer.

Another variant in the same gene was just shy of genome-wide significance, while more than a dozen other SNPs in the same region had nominal associations with cisplatin-related ototoxicity.

Those involved in the study noted that past research has implicated ACYP2 variants in neuropathy risk amongst individuals treated with another platinum-based therapy called oxaliplatin.

Still, they cautioned that additional variants — either in ACYP2 or other genes — are likely involved in cisplatin-related ototoxicity risk, highlighting the importance of future fine-mapping studies in larger groups of cisplatin-treated patients.