Lee John J W, Latif Asna, Scott Erika N, Thakral Abhinav, Mahler Mary B, Brooks Beth, Hueniken Katrina, Billfalk-Kelly Astrid, Espin-Garcia Osvaldo, Zhan Luna Jia, Rassekh S Rod, Pecheux Lucie, Spavor Maria, Li Yuling, Goldstein David, Hope Andrew, Ross Colin J, Liu Geoffrey, Carleton Bruce C, Bhavsar Amit P
Department of Otolaryngology-Head and Neck Surgery, Sinai Health System, Toronto, Ontario, Canada.
Department of Medical Microbiology and Immunology, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.
J Pharmacol Exp Ther. 2025 Feb;392(2):100057. doi: 10.1016/j.jpet.2024.100057. Epub 2024 Dec 9.
Cisplatin causes permanent hearing loss or cisplatin-induced ototoxicity in over 50% of treated patients with cancer, leading to significant social and functional limitations. Interindividual variability in developing hearing loss suggests the role of genetic predispositions to cisplatin-induced hearing loss. We investigated genetic associations between cisplatin-induced ototoxicity and toll-like receptor 4 (TLR4), an immune receptor known to mediate inflammatory responses to cisplatin. Using a case-control candidate gene approach, we identified 20 single nucleotide polymorphisms at the TLR4 locus with significant protection against ototoxicity in a cohort of 213 adult patients, followed by an independent pediatric patient cohort (n = 357). Combined cohort analysis demonstrated a significant association between cisplatin-induced ototoxicity protection and a single variant in the TLR4 promoter, rs10759932. We showed that rs10759932 downregulated TLR4 expression that is normally induced by cisplatin. This work provides pharmacogenetic and functional evidence to implicate TLR4 with cisplatin-induced hearing loss in patients. SIGNIFICANCE STATEMENT: Adult and pediatric patients carrying toll-like receptor 4 (TLR4) genetic variants were protected against developing cisplatin-induced hearing loss following cisplatin treatment. Important variants in the TLR4 promoter disrupted a drug-gene interaction between cisplatin and TLR4, mirroring the protective effect conferred by genetic inhibition of TLR4. These variants have the potential to improve the prediction of cisplatin toxicity, allowing for more precise chemotherapy treatment.
顺铂会导致超过50%的癌症患者出现永久性听力丧失或顺铂诱导的耳毒性，从而导致严重的社会和功能限制。个体间听力丧失的差异表明存在遗传易感性导致顺铂诱导听力丧失的作用。我们研究了顺铂诱导的耳毒性与Toll样受体4（TLR4）之间的遗传关联，TLR4是一种已知可介导对顺铂炎症反应的免疫受体。采用病例对照候选基因方法，我们在213名成年患者队列中确定了TLR4基因座上20个单核苷酸多态性对耳毒性具有显著保护作用，随后是一个独立的儿科患者队列（n = 357）。联合队列分析表明，顺铂诱导的耳毒性保护与TLR4启动子中的一个单变体rs10759932之间存在显著关联。我们发现rs10759932下调了通常由顺铂诱导的TLR4表达。这项工作提供了药物遗传学和功能证据，表明TLR4与患者顺铂诱导的听力丧失有关。意义声明：携带Toll样受体4（TLR4）基因变异的成年和儿科患者在顺铂治疗后可免受顺铂诱导的听力丧失。TLR4启动子中的重要变体破坏了顺铂与TLR4之间的药物-基因相互作用，反映了TLR4基因抑制所赋予的保护作用。这些变体有可能改善对顺铂毒性的预测，从而实现更精确的化疗治疗。
