Study Explores Link Between Genetic Mutations and Cisplatin-Induced Hearing Loss in Cancer Survivors

Almost all patients who are treated with cisplatin experience some form of hearing loss after treatment, whether it be temporary or permanent. 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 Wheeler, an assistant professor of Biology and Computer Science 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 Annual Meeting of the American Society of Clinical Oncology (ASCO), a gathering of 30,000 oncology professionals in Chicago.

Can you give an overview of the study?

CURE spoke to Wheeler to discuss the significance of this finding and what the future holds for this research.We know one of the side effects of cisplatin treatment is hearing loss and testicular cancer survivors are typically young men who have undergone treatment for testicular cancer with the drug. About 80 percent of them experience some form of hearing loss and in 18 percent, 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. We proceeded to do a genome-wide association study, which means we looked at genetic variants across the genome. In a cohort of testicular cancer survivors, researchers collected hearing threshold data. They performed 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 the genetics of treatment-based 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?

Why did you hone in on testicular cancer survivors?

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.What’s great about this particular cohort is that the regimens of treatments are much more standard than other types of cancer. 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?

Severe mutations in the WFS1 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 genomes, 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. Patients and survivors should know there are side effects to the therapy, but cisplatin is really good at treating testicular cancer. There are management possibilities after they undergo the chemotherapy. Patients should tell their doctor if they are experiencing hearing loss because they can get help.

What constitutes hearing loss as severe or profound?

What are some questions regarding hearing loss and testicular cancer remain unanswered?

There’s different criteria defined by the American Speech-Language-Hearing Association. They categorize severe as a certain threshold of hearing, so at a particular frequency someone with hearing loss won’t be able to hear that tone. 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. In the electronic medical records, it wasn’t just cancer patients, it was anyone who had a hearing loss phenotype.

For us, it’s more 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 that are 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.