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

Affiliations

PMID: 32998964
DOI: 10.1158/1078-0432.CCR-20-2682

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 GWAS (cases: 104; controls: 196) was also performed.

Results: Age at clinical examination (p=6.4x10-16) and cumulative cisplatin dose (p=5.4x10-4) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (p=0.02), tobacco use (ever smoker: p=0.001, 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=3.7x10-9), and symptoms consistent with peripheral motor neuropathy (p=4.3x10-14) after age- and dose-adjustment. These patients also reported poorer overall health (p=2.7x10-5) and a greater use of psychotropic medications (p=0.06). GWAS identified no genome-wide significant SNPs. Gene-based association analysis identified RGS17 (p=3.9x10-5) and FAM20C (p=5.5x10-5) 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.