Nakshatri Swetha, Dinh Paul C, Einhorn Lawrence H, Feldman Darren R, Hamilton Robert J, Vaughn David J, Fung Chunkit, Kollmannsberger Christian, Huddart Robert A, Travis Lois B, Cox Nancy J, Dolan M Eileen
Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Department of Medical Oncology, Indiana University, Indianapolis, Indiana, USA.
Cancer Med. 2025 Sep;14(17):e71218. doi: 10.1002/cam4.71218.
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.
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.
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.
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. For neuropathy, rs34904346 (p = 2.0 × 10) 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) 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.
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.
顺铂是一种广泛应用于多种癌症类型的化疗药物，可导致患者出现神经毒性，包括周围感觉神经病变、耳鸣、听力丧失和眩晕。
我们旨在首次评估遗传血统如何影响顺铂诱导的神经毒性，以及这些差异是否与等位基因频率的人群差异有关。
在一组接受顺铂治疗的睾丸癌幸存者队列中，使用逻辑回归和Kruskal-Wallis检验评估遗传血统与神经毒性、药物和生活方式因素之间的关系，并使用Wilcoxon秩和检验（Benjamini-Hochberg校正）进行多次两两比较。计算单核苷酸多态性（SNP）基因型与具有显著人群差异的神经毒性之间的关联，以识别与毒性相关的具有人群等位基因频率分化的独立功能变异。
在进行四个周期的基于顺铂的化疗后，与欧洲和亚洲血统的幸存者相比，非洲血统的幸存者出现神经病变和眩晕的可能性显著更高，尽管亚洲血统的幸存者在评估时比其他血统的幸存者年轻得多。在对人群等位基因频率分化、功能相关性和独立性进行筛选后，对19,992个SNP进行了毒性关联测试。虽然没有一个通过Bonferroni阈值，但分别有两个和四个SNP与神经病变和眩晕相关，p值具有提示性显著性（p < 1.0 × 10）。对于神经病变，rs34904346（p = 2.0 × 10）是神经组织中RNF24的表达数量性状位点（eQTL），另外三个RNF24 eQTL与神经病变相关（p < 0.01）。对于眩晕，rs3777909（p = 3.1 × 10）是神经组织中MFSD4B和脑组织中REV3L的eQTL，另外还有三个MFSD4B的eQTL和四个REV3L的eQTL与眩晕相关（p < 0.05）。在计算机模拟中，癌细胞系中较高的MFSD4B和REV3L表达与显著更高的顺铂敏感性相关。
与欧洲血统相比，非洲血统与顺铂诱导的周围感觉神经病变和眩晕增加有关。人群等位基因频率差异以及RNF24、MFSD4B和REV3L的表达水平可能与之相关。
