Introduction Cisplatin is a cornerstone chemotherapeutic agent frequently associated with dose-limiting ototoxicity. Increasing evidence suggests that immune-mediated mechanisms may influence interindividual susceptibility to this adverse effect; however, the role of inherited immune traits remains poorly understood. Aim This study aimed to evaluate the causal relationship between 33 inherited immune traits and cisplatin-induced ototoxicity using Mendelian randomization (MR), and to identify age-stratified susceptibility markers in pediatric and adult cancer survivors. Method MR was used to assess the causal effects of genetically predicted immune traits on cisplatin-induced ototoxicity. Single-nucleotide polymorphisms associated with immune traits were selected from large-scale genome-wide association study datasets. The primary analysis used the inverse variance weighted method with MR-Egger, weighted median, weighted mode, and MR-PRESSO as the sensitivity approaches. Bidirectional MR and sensitivity analyses were conducted to assess robustness and rule out reverse causation. Bonferroni correction was employed to minimize potential false-positive findings (P < 0.05/165 ≈ 0.0003). Results Transforming Growth Factor-beta principal component analysis (TGF-β PCA) showed an age-stratified effect: it was associated with increased risk of hearing loss in pediatric patients (OR (95% CI): 1.0 × 101 (1.6 × 100–6.6 × 101), P = 0.014) but conferred strong protection against Speech Recognition Threshold (SRT) impairment (OR (95% CI): 2.8 × 10⁻1 (1.4 × 10⁻1–5.3 × 10⁻1), P = 0.00012) and hearing loss (OR (95% CI): 4.7 × 10⁻1 (2.7 × 10⁻1–8.1 × 10⁻1), P = 0.006) in adults. Additional protective associations have been identified for T Central Memory (TCM) cells and Programmed Cell Death Protein-1 (PD-1) in adults. Reverse MR analysis excluded significant reverse causation. Following Bonferroni correction, the association between TGF-β PCA and SRT remained statistically significant (P < 0.0003) in the adult cohort. However, all other associations in adults and the entire pediatric cohort demonstrated only nominal significance (0.0003 ≤ P < 0.05). Conclusion Inherited immune traits, particularly TGF-β PCA, PD-1, and TCM cells, exhibit age-stratified causal effects on cisplatin-induced ototoxicity. These findings suggest the use of immunogenetic profiling for risk prediction and personalized strategies in oncology pharmacy practice.

Inherited immune traits and cisplatin-induced ototoxicity in cancer patients: a Mendelian randomization study

期刊论文
发表日期：

2025年11月20日

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Yang Zheng,
Xin Yang,
Shangjun Hua,
Qimei Fang,
Di Li

摘要

Introduction

Cisplatin is a cornerstone chemotherapeutic agent frequently associated with dose-limiting ototoxicity. Increasing evidence suggests that immune-mediated mechanisms may influence interindividual susceptibility to this adverse effect; however, the role of inherited immune traits remains poorly understood.

Aim

This study aimed to evaluate the causal relationship between 33 inherited immune traits and cisplatin-induced ototoxicity using Mendelian randomization (MR), and to identify age-stratified susceptibility markers in pediatric and adult cancer survivors.

Method

MR was used to assess the causal effects of genetically predicted immune traits on cisplatin-induced ototoxicity. Single-nucleotide polymorphisms associated with immune traits were selected from large-scale genome-wide association study datasets. The primary analysis used the inverse variance weighted method with MR-Egger, weighted median, weighted mode, and MR-PRESSO as the sensitivity approaches. Bidirectional MR and sensitivity analyses were conducted to assess robustness and rule out reverse causation. Bonferroni correction was employed to minimize potential false-positive findings (P < 0.05/165 ≈ 0.0003).

Results

Transforming Growth Factor-beta principal component analysis (TGF-β PCA) showed an age-stratified effect: it was associated with increased risk of hearing loss in pediatric patients (OR (95% CI): 1.0 × 10¹ (1.6 × 10⁰–6.6 × 10¹), P = 0.014) but conferred strong protection against Speech Recognition Threshold (SRT) impairment (OR (95% CI): 2.8 × 10⁻¹ (1.4 × 10⁻¹–5.3 × 10⁻¹), P = 0.00012) and hearing loss (OR (95% CI): 4.7 × 10⁻¹ (2.7 × 10⁻¹–8.1 × 10⁻¹), P = 0.006) in adults. Additional protective associations have been identified for T Central Memory (TCM) cells and Programmed Cell Death Protein-1 (PD-1) in adults. Reverse MR analysis excluded significant reverse causation. Following Bonferroni correction, the association between TGF-β PCA and SRT remained statistically significant (P < 0.0003) in the adult cohort. However, all other associations in adults and the entire pediatric cohort demonstrated only nominal significance (0.0003 ≤ P < 0.05).

Conclusion

Inherited immune traits, particularly TGF-β PCA, PD-1, and TCM cells, exhibit age-stratified causal effects on cisplatin-induced ototoxicity. These findings suggest the use of immunogenetic profiling for risk prediction and personalized strategies in oncology pharmacy practice.