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

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 cisplatintreated testicular cancer survivors using logistic regression. Casecontrol genome-wide association study (GWAS; cases, n ¼ 104 and controls, n ¼ 196) was also performed.Results: Age at clinical examination (P ¼ 6.4 Â 10 À16 ) and cumulative cisplatin dose (P ¼ 5.4 Â 10 À4 ) were positively associated with multiple severe neurotoxicity risk, as were high serum platinum levels (P ¼ 0.02), tobacco use (ever smoker, P ¼ 0.001 and current smoker, P ¼ 0.002), and hypertension (P ¼ 0.01) after adjustment for age and cumulative cisplatin dose. Individuals with multiple severe neurotoxicities were more likely to experience dizziness/vertigo (P ¼ 0.01), Raynaud phenomenon (P ¼ 3.7 Â 10 À9 ), and symptoms consistent with peripheral motor neuropathy (P ¼ 4.3 Â 10 À14 ) after age and dose adjustment. These patients also reported poorer overall health (P ¼ 2.7 Â 10 À5 ) and a greater use of psychotropic medications (P ¼ 0.06). GWAS identified no genomewide significant SNPs. Gene-based association analysis identified RGS17 (P ¼ 3.9 Â 10 À5 ) and FAM20C (P ¼ 5.5 Â 10 À5 ) 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 cisplatininduced 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.

Pharmacogenomics of cisplatin‐induced neurotoxicities: Hearing loss, tinnitus, and peripheral sensory neuropathy

“…Continued smoking in patients with cancer is associated with significant incremental costs for further cancer treatment when first‐line therapy fails 44 . In addition, previous investigations also demonstrated significant increases in the neurotoxic effects of chemotherapy in smokers, supporting the findings of the current study 12,45 . The 2020 Surgeon General's Report 46 indicates that smoking cessation improves patients' quality of life and adds up to 10 years to their lifespan.…”

“…44 In addition, previous investigations also demonstrated significant increases in the neurotoxic effects of chemotherapy in smokers, supporting the findings of the current study. 12,45 The 2020 Surgeon General's Report 46 indicates that smoking cessation improves patients' quality of life and adds up to 10 years to their lifespan. In addition, with clear evidence that smoking cessation is beneficial both before and after cancer treatment for many cancer types, this report 46 Cisplatin-based therapy consists primarily of either three cycles of BEP or four cycles of EP resulting in a cumulative dose of 300 or 400 mg/m 2 cisplatin, respectively although occasional patients may receive doses of cisplatin greater than 400 mg/m 2 .…”

Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease

“…RGS17 was reported as a negative modulator of G-protein-coupled receptor signals in several cancers, 33 and the variants of RGS17 were recently reported to be associated with cisplatin-induced neurotoxicities via a gene-based analysis of the results of a GWAS. 34 It was interesting to find that the genetic variants of RGS17 are associated with drug-induced adverse events, but there is no report about the role of RGS17 in IBD or mesalamine pharmacokinetics. Moreover, we discovered that an SNP exists very close to RP11-306O13.1, which is a long intergenic noncoding RNA.…”

Regulation of secretory pathway kinase or kinase-like proteins in human cancers

“…This result has been recognized by peers ( 61 , 62 ). It was also found that increased FAM20C expression is related to decreased cisplatin sensitivity in testicular cancer ( 63 ).…”