Impact of Population Pharmacogenomics on Cisplatin-Induced Neurotoxicities in Testicular Cancer Survivors

Background

Cisplatin is a commonly used chemotherapeutic across numerous cancer types that can cause neurotoxicities in patients, including peripheral sensory neuropathy, tinnitus, hearing loss, and vertigo.

Objective

We aimed to evaluate, for the first time, how genetic ancestry impacts cisplatin-induced neurotoxicities and if disparities are related to population differences in allele frequency.

Methods

In a cohort of cisplatin-treated testicular cancer survivors, relationships between genetic ancestry and neurotoxicities, medications, and lifestyle factors were assessed using logistic regression and Kruskal–Wallis tests and multiple pairwise comparisons using the Wilcoxon rank-sum test (Benjamini–Hochberg adjustment). Associations between single nucleotide polymorphism (SNP) genotypes and neurotoxicities with significant inter-population disparities were calculated to identify independent, functional variants with population allele frequency differentiation associated with toxicities.

Results

Following four cycles of cisplatin-based chemotherapy, African ancestry survivors were significantly more likely to have neuropathy and vertigo versus European and Asian-axis ancestry survivors, although Asian axis survivors were significantly younger at evaluation than other ancestries. Following filtering for population allele frequency differentiation, functional relevance, and independence, 19,992 SNPs were tested for association with toxicities. Although none passed the Bonferroni threshold, two and four SNPs were associated with neuropathy and vertigo, respectively, at suggestively significant p < 1.0 × 10⁻⁴. For neuropathy, rs34904346 (p = 2.0 × 10⁻⁵) was an expression quantitative trait locus (eQTL) for RNF24 in nerve tissue, with three other RNF24 eQTLs associated with neuropathy (p < 0.01). For vertigo, rs3777909 (p = 3.1 × 10⁻⁵) was an eQTL for MFSD4B in nerve and REV3L in brain tissue, along with three other eQTLs for MFSD4B and four for REV3L associated with vertigo (p < 0.05). In silico, higher MFSD4B and REV3L expression in cancer cell lines were associated with significantly greater cisplatin sensitivity.

Conclusion

African ancestry was associated with increased cisplatin-induced peripheral sensory neuropathy and vertigo versus European ancestry. Population allele frequency differences and expression levels of RNF24, MFSD4B, and REV3L were potentially implicated.