| Abstract: |
Purpose: Cisplatin is a first-line chemotherapeutic for many cancers, but causes neurotoxicity including hearing loss, tinnitus, and peripheral sensory neuropathy. However, no study has comprehensively characterized risk factors for developing multiple (>1) severe neurotoxicities. Experimental Design: The relationship between multiple severe neurotoxicities and age, cumulative cisplatin dose, medical history, and lifestyle/behavioral factors was evaluated in 300 cisplatin-treated testicular cancer survivors using logistic regression. Case-control genome-wide association study (GWAS; cases, n 1⁄4 104 and controls, n 1⁄4 196) was also performed. Results: Age at clinical examination (P 1⁄4 6.4 * 10-16) and cumulative cisplatin dose (P 1⁄4 5.4 * 10-4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P 1⁄4 0.02), tobacco use (ever smoker, P 1⁄4 0.001 and current smoker, P 1⁄4 0.002), and hypertension (P 1⁄4 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P 1⁄4 0.01), Raynaud phenomenon (P 1⁄4 3.7 * 10-9), and symptoms consistent with peripheral motor neuropathy (P 1⁄4 4.3 * 10-14) after age and dose adjustment. These patients also reported poorer overall health (P 1⁄4 2.7 * 10-5) and a greater use of psychotropic medications (P 1⁄4 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (P 1⁄4 3.9 * 10-5) and FAM20C (P 1⁄4 5.5 * 10-5) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines. Conclusions: Certain survivors are more susceptible to cisplatin-induced neurotoxicity, markedly increasing likelihood of developing numerous neuro-otological symptoms that affect quality of life. Genome-wide analysis identified genetic variation in FAM20C as a potentially important risk factor. © 2020 American Association for Cancer Research. |
