Cisplatin is a highly effective chemotherapeutic agent for children with certain solid tumors. Unfortunately, ototoxicity—when a patient develops hearing loss due to a medication—is a common adverse event of cisplatin treatment and remains a serious clinical challenge. 1 Previous studies have shown up to 60% of children treated with cisplatin suffer irreversible hearing loss. 2
The significant heterogeneity in the incidence of ototoxicity among comparably treated patients indicates that genetic susceptibility contributes to cisplatin-related hearing loss. Thus, an unmet need is understanding the biology of cisplatin--induced hearing loss (CIHL) and identifying risk factors that could predict ototoxicity.
To gain better insight into the course of CIHL, an international study led by the European organization PanCareLIFE investigated how the genetic variations in 770 pediatric patients in Europe and Canada influenced their response to cisplatin. The findings of the study were published in Precision Oncology. 3
The researchers retrospectively reviewed data on 368 Canadian childhood cancer patients (52% male; 38% aged 5 years) who underwent a total of 2,052 audiological assessments (median, 5; range, 2-15) before, during, and after cisplatin therapy. Audiological assessments were performed to examine the effects of CIHL for up to three years after the start of treatment. The investigators graded hearing loss according to International Society of Pediatric Oncology criteria and utilized the Kaplan-Meier method to assess the cumulative incidence of CIHL for the overall cohort, as well as according to age.
The findings revealed an overall cumulative incidence of CIHL of 59.7% (95% CI, 51.4-68.1) at three years after treatment initiation. Additionally, children aged 5 years or younger who received cisplatin chemotherapy had a higher incidence of CIHL than children older than 5 years (75% vs. 48%; P <.001). Of note, the rate of hearing loss quickly increased among the younger cohort at three months (27%; 95% CI, 21-35) and at one year (61%; 95% CI, 53-69). The study also looked at concomitant drugs, and their effects on hearing loss in child patients with cancer. According to a multivariate Cox regression model, factors that exacerbated CIHL over time included total cumulative dose of cisplatin at three months during therapy (per 100 mg/m² increase: hazard ratio ((HR) = 1.2; 95% CI, 1.01-1.41), co-prescriptions of the chemotherapy drug vincristine (HR = 2.87, 95% CI, 1.89-4.36) and longer duration of concomitantly administered antibiotics (>30 days: HR = 1.85, 95% CI, 1.17-2.95).
The heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Utilizing a genome-wide association study (GWAS) approach, the researchers identified a genetic variant in TCERG1L (rs893507) to be associated to an increase the risk of CIHL.
The findings from this first cohort study were strengthened through replication in two independent similarly treated cohorts (n = 192 and 188, respectively). Combined analysis of these three cohorts revealed that cisplatin-treated, non--cranial irradiated childhood cancer patients with a genetic intronic variant (rs893507) in TCERG1L have a 3.11-fold increased odds of developing CIHL. Next, in vitro validation studies were performed in the lab of Amit Bhavsar, PhD, at the University of Alberta. The team manipulated TCERG1L gene expression in cultured human cells to investigate the effect of TCERG1L expression on cisplatin cytotoxicity and inflammatory response. Their laboratory findings revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity.
The Hearing Journal connected with authors Ivan Kristell Domingo and Amit Bhavsar, PhD, to further discuss their work. Bhavsar, an Assistant Professor in the Department of Medical Microbiology & Immunology and Canada Research Chair in Functional Genomic Medicine, led the research team that confirmed the study’s genomic findings with a biological investigation using cell-based models.
THJ: In terms of audiological assessments, what is the significance and clinical implications of this study?
Domingo and Bhavsar: The study supports the idea that there are genetic conditions that may predispose certain individuals, especially children, to CIHL. Identifying the genetic factors that can put pediatric cancer patients more, or less, at risk, of hearing loss caused by cisplatin, would allow clinicians to make more informed decisions ahead of time. For example, a pediatric cancer patient known to possess the rs893507 variant of TCERG1L could be treated with lower doses of cisplatin or have their hearing actively monitored during and after treatment.
THJ: What are some potential underlying mechanisms that may contribute to the higher incidence of CIHL among very young children?
Domingo and Bhavsar: CIHL develops in at least half of all patients treated with cisplatin—irrespective of age—but several studies over the years have determined that children below the age of 5 are especially susceptible. Unfortunately, our understanding of why young children are, according to literature, up to 8x more likely to experience CIHL, remains incomplete. Investigations suggest that differences in susceptibility to CIHL in general are related to differences in the expression and functionality of genes, some of which may facilitate cisplatin uptake. For example, copper transporters, are more highly expressed in children compared to adults. In general, children do tend to be more susceptible to drug toxicities overall and it is likely that there are common reasons why that is—whether it is differences in gene expression, or the profound development children undergo as they mature.
THJ: Regarding concomitant drugs with cisplatin and their effects on hearing loss in child patients with cancer, were there any assessment of ototoxic co-medications and their potential influence on the strength of the TCERG1L genetic association?
Domingo and Bhavsar: The clinical data acquired and analyzed across three patient cohorts did not account for ototoxic co-medications because that information was not always reported consistently in patient charts. However, patients that received cranial irradiation co-therapy were not included in the study to specifically remove cranial irradiation as a confounding variable. Cranial irradiation co-therapy is known to cause hearing loss independently. By excluding it, the study was able to identify a genetic marker for hearing loss specifically associated with cisplatin treatment—independent of cranial irradiation. Whether ototoxic co-medications or cranial irradiation enhance or suppress the effects of TCERG1L genetic variation remains to be studied.
THJ: As TCERG1L is a transcription regulator, is any additional research being conducted to investigate other genes regulated by TCERG1L to see what role they play in CIHL?
Domingo and Bhavsar: It is certainly an extremely promising avenue of research for cisplatin-induced toxicities and related fields overall. TCERG1L/TCERG1 has been linked to various immunological diseases and is believed to operate by modifying not gene expression directly, but mRNA transcription. An improved understanding of how TCERG1L works or which genes it influences, could grant us access to novel means of controlling the underlying processes that contribute to CIHL.
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1. Yu D, Gu J, Chen Y, et al. 2020 Current strategies to combat cisplatin-induced ototoxicity Front Pharmacol ■ ■ https://doi.org/10.3389/fphar.2020.00999
2. Mukherjea D, Rybak LP 2011 Pharmacogenomics of cisplatin-induced ototoxicity Pharmacogenomics 12 1039 50 https://dx.doi.org/10.2217%2Fpgs.11.48
3. Meijer AJM, Diepstraten F A, Langer T, et al. 2021 TCERG1L
allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study
npj Precision Oncology ■ ■ https://doi.org/10.1038/s41698-021-00178-z