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Genetic Mutation Could Play Role in Cisplatin-Induced Hearing Loss

By Ellie Leick
Heather Wheeler, PhD

Dr. Heather Wheeler, PhD

Treatment with cisplatin results in a high instance of some form of hearing loss for most patients. A study researching the genetics behind the hearing loss was recently conducted with the hope that physicians will be able to foresee who will experience hearing loss so they could adjust treatment accordingly.

Headed by Heather E. Wheeler, PhD, an assistant professor at Loyola University in Chicago, the study focused on a group of 512 survivors of testicular cancer who experienced hearing loss. Researchers found the WFS1 gene was associated with cisplatin-related hearing loss, a finding they expect to transfer across other types of cancers. Wheeler presented the study’s findings at the 2016 ASCO Annual Meeting, where Oncology Nursing News spoke with Wheeler about the significance of this finding and what the future holds for this research.

Please provide an overview of the study.
We know one of the side effects of cisplatin treatment is hearing loss. Testicular cancer survivors are typically young men who have undergone treatment for testicular cancer with the drug cisplatin. About 80% of them experience some form of hearing loss, and in 18%, it can be severe to profound hearing loss. We were interested in understanding the genetics of this variation and exploring the reasons why some patients experience extreme hearing loss and others experience just a bit, so we proceeded to do a genome-wide association study, which looks at genetic variants across the genome. 

In a cohort of testicular cancer survivors, researchers collected hearing threshold data. They performed a range of hearing tests on the survivors at a range of frequencies up to 12 kilohertz and developed a phenotype of hearing loss we could use in our genome-wide association study. 

Why did you want to look at genetics of treatment-related hearing loss?
The long-term goal of genetics studies is to understand the underlying biological mechanisms that are causing hearing loss. If we can find variants that associate with a particular trait, it can help us understand the biology. Maybe someday we will be able to predict who is going to experience the hearing loss more severely than someone else and adjust the treatment accordingly. 

Is there any correlation between the amount of cisplatin received and the level of hearing loss?
We have a paper coming out in the Journal of Clinical Oncology that looks at this cohort of testicular cancer survivors and finds that those who have higher doses of cisplatin also have more severe hearing loss. It’s been shown previously as well. 

Why did you hone in on testicular cancer survivors?
What’s great about this particular cohort is that their treatment regimens are more standard than other those for other cancer types. Any patient with testicular cancer that undergoes chemotherapy receives cisplatin. We’re also concerned with survivorship issues in this cohort because they’re typically younger than other patients with cancer. 

What are the key takeaways of this study?
In the study we found a variant that is in WSF1 that is associated with increased hearing loss in these testicular cancer survivors. The same variant is also associated with decreased expression of this gene WSF1. More severe mutations in this gene cause Wolfram syndrome, which is a disorder characterized by multiple phenotypes; one of them is deafness. It made a lot of sense that as we’re looking at hearing loss, we find a gene that’s known to be implicated in deafness. 

We looked deeper into our data because we have genotype data across the genome, so we looked at other genes that cause deafness when they’re severely mutated. We saw an enrichment of variations in those genes leading to increased hearing loss in our testicular cancer cohorts. Even though these patients aren’t going completely deaf, the same underlying biological mechanisms that cause deafness may be involved in their hearing loss. We can learn something about it through the genome-wide association study. 

What are some questions regarding hearing loss and testicular cancer that you still want answered?
Our study is great because we have a fantastic cohort of survivors who were very well-phenotyped in terms of their hearing loss. We were able to look in electronic medical records, where we also had genome-wide genotypes and replicator association in this particular gene, WFS1. These electronic medical records did not just include cancer patients, but any patient who had a hearing loss phenotype. 

For us, the goal is to increase our understanding the genetics of hearing loss. Yes, this one gene is involved, but it looks like other genes are involved as well, so it’s a lot more complex than we thought. I don’t think there’s going to be one gene that physicians can genotype to figure out a patient’s risk of hearing loss, but by looking at cohorts like testicular cancer, we can learn a lot about the hearing loss phenotype. 

Are these findings significant to other cancers treated with cisplatin?
Our results have implications for anyone who is treated with cisplatin. Cisplatin is used a lot in pediatric cancers as well. Their hearing loss can be even more devastating because if they’re very young patients they haven’t even learned to talk yet. If they’re having trouble hearing, that’s going to affect their whole life. Our findings in the testicular cancer cohort may have implications in cohorts such as those as well. 
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