Systematic Review and Meta‐analysis of the Influence of Genetic Variation on Ototoxicity in Platinum‐Based Chemotherapy

Abstract

Objective The objective of this meta‐analysis is to evaluate the impact of genetic polymorphisms on platinum‐based chemotherapy (PBC)‐induced ototoxicity. Data Sources Systematic searches of PubMed, Embase, Cochrane, and Web of Science were conducted from the inception of the databases to May 31, 2022. Abstracts and presentations from conferences were also reviewed. Review Methods Four investigators independently extracted data in adherence to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. Differences in the prevalence of PBC‐induced ototoxicity between reference and variant (i) genotypes and (ii) alleles were analyzed. The overall effect size was presented using the random‐effects model as an odds ratio (OR) with a 95% confidence interval (CI). Results From 32 included articles, 59 single nucleotide polymorphisms on 28 genes were identified, with 4406 total unique participants. For allele frequency analysis, the A allele in ACYP2 rs1872328 was positively associated with ototoxicity (OR: 2.61; 95% CI: 1.06‐6.43; n = 2518). Upon limiting to cisplatin use only, the T allele of COMT rs4646316 and COMT rs9332377 revealed significant results. For genotype frequency analysis, the CT/TT genotype in ERCC2 rs1799793 demonstrated an otoprotective effect (OR: 0.50; 95% CI: 0.27‐0.94; n = 176). Excluding studies using carboplatin or concomitant radiotherapy revealed significant effects with COMT rs4646316, GSTP1 rs1965, and XPC rs2228001. Major sources of variations between studies include differences in patient demographics, ototoxicity grading systems, and treatment protocols. Conclusion Our meta‐analysis presents polymorphisms that exert ototoxic or otoprotective effects in patients undergoing PBC. Importantly, several of these alleles are observed at high frequencies globally, highlighting the potential for polygenic screening and cumulative risk evaluation for personalized care.