Clinical and Genome-Wide Analysis of Multiple Severe Cisplatin-Induced Neurotoxicities in Adult-Onset Cancer Survivors.

Abstract

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. 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, <i>n</i> = 104 and controls, <i>n</i> = 196) was also performed. Age at clinical examination (<i>P</i> = 6.4 × 10^-16) and cumulative cisplatin dose (<i>P</i> = 5.4 × 10^-4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (<i>P</i> = 0.02), tobacco use (ever smoker, <i>P</i> = 0.001 and current smoker, <i>P</i> = 0.002), and hypertension (<i>P</i> = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (<i>P</i> = 0.01), Raynaud phenomenon (<i>P</i> = 3.7 × 10^-9), and symptoms consistent with peripheral motor neuropathy (<i>P</i> = 4.3 × 10^-14) after age and dose adjustment. These patients also reported poorer overall health (<i>P</i> = 2.7 × 10^-5) and a greater use of psychotropic medications (<i>P</i> = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified <i>RGS17</i> (<i>P</i> = 3.9 × 10^-5) and <i>FAM20C</i> (<i>P</i> = 5.5 × 10^-5) as near genome-wide significant. Decreased <i>FAM20C</i> expression was associated with increased cisplatin sensitivity in tumor cell lines. 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 <i>FAM20C</i> as a potentially important risk factor.