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

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>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 (&gt;1) severe neurotoxicities.</jats:p> </jats:sec> <jats:sec> <jats:title>Experimental Design:</jats:title> <jats:p>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 = 104 and controls, n = 196) was also performed.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Age at clinical examination (P = 6.4 × 10−16) and cumulative cisplatin dose (P = 5.4 × 10−4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P = 0.02), tobacco use (ever smoker, P = 0.001 and current smoker, P = 0.002), and hypertension (P = 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P = 0.01), Raynaud phenomenon (P = 3.7 × 10−9), and symptoms consistent with peripheral motor neuropathy (P = 4.3 × 10−14) after age and dose adjustment. These patients also reported poorer overall health (P = 2.7 × 10−5) and a greater use of psychotropic medications (P = 0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (P = 3.9 × 10−5) and FAM20C (P = 5.5 × 10−5) as near genome-wide significant. Decreased FAM20C expression was associated with increased cisplatin sensitivity in tumor cell lines.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> </jats:sec>