Mitochondrial DNA Variation and Platinum-Induced Ototoxicity in Humans: A Systematic Evidence Map and Research Agenda

Background: Platinum chemotherapy causes irreversible sensorineural hearing loss in a large fraction of treated patients. Inherited mitochondrial DNA (mtDNA) variation—most famously the 12S rRNA m.1555A>G mutation—is an established cause of aminoglycoside ototoxicity and has motivated clinical genotype-guided screening. Whether mtDNA variation similarly predisposes to platinum-induced ototoxicity remains unresolved, despite a strong mechanistic rationale: cisplatin forms adducts on mtDNA, mitochondria lack nucleotide excision repair, and platinum exposure can be chronic. Objective: To systematically map all human evidence linking inherited mtDNA variation to platinum-associated hearing loss, quantify the evidence base, and formalize a research agenda. Methods: Six PubMed strategies plus backward/forward citation chaining (five seeds), replicated in Embase, Web of Science, Scopus, CNKI, and WanFang (19/20 October 2026 update), identified 3942 records; after duplicate removal (within-database and cross-database), 2101 unique records were screened by a rule-assisted title/abstract process (exclusion audits: 100 randomly sampled exclusions plus a targeted near-miss audit of 100 records carrying 2–3 of the four eligibility concept classes; zero core-criterion misses in both). Eligible Tier-1 studies required direct mtDNA genotyping, platinum exposure, and a hearing outcome in humans. Results: Fifteen reports advanced to full-text triage: fourteen from the PubMed pool (four Tier-1 genotyped cohort studies, total n = 183; one Tier-2 report; and nine excluded with reasons) plus one Tier-1 case report not indexed in PubMed, identified through expert consultation and retrospectively located in the Embase replication search, verified in full text. Spanning 2003–2021, the evidence base comprises three cohorts that are uninformative rather than null for the m.1555A>G question (zero carriers; no association testable), one unreplicated, hypothesis-generating cohort-level signal (haplogroup J enrichment 5/20 vs. 1/19; Fisher exact OR 6, 95% CI 0.6–57, p = 0.18), and one positive case report (a homoplasmic m.1555A>G carrier who developed bilateral hearing loss two weeks after cisplatin-based chemotherapy). Among 111 patients genotyped for canonical deafness-associated mtDNA variants (m.1555A>G was tested in all three studies), zero m.1555A>G carriers were observed; the sole reported m.1555A>G carrier in the context of platinum exposure is that single case report. One Tier-2 study (n = 85) documented pre-treatment familial high-frequency hearing loss in 15/85 testicular cancer patients without genotyping. No two studies reported comparable genotype-stratified 2 × 2 data; therefore, no pooled estimate exists, and none can currently be computed. An evidence-gap map shows that the aminoglycoside paradigm progressed from case reports to guideline-level screening in three decades, whereas the mechanistically analogous platinum question has not advanced past small, mostly negative observational studies. Conclusions: The human evidence base for mtDNA genotype-stratified platinum ototoxicity is systematically thin—not because the hypothesis has been refuted, but because no adequately powered, prospective, genotype-stratified study has been performed. We propose a concrete agenda for closing this gap—pre-treatment mitochondrial genotyping embedded in existing aminoglycoside screening pipelines and survivorship biobanks—and release a curated map of public datasets suitable for mechanism work.