Abstract
Purpose: Adverse drug reactions such as ototoxicity, which occurs in approximately one-fifth of adult patients who receive cisplatin treatment, can incur large socioeconomic burdens on patients with testicular cancer who develop this cancer during early adulthood. Recent genome-wide association studies have identified genetic variants in ACYP2 and WFS1 that are associated with cisplatin-induced ototoxicity. We sought to explore the role of these genetic susceptibility factors to cisplatin-induced ototoxicity in patients with testicular cancer.Experimental Design: Extensive clinical and demographic data were collected for 229 patients with testicular cancer treated with cisplatin. Patients were genotyped for two variants, ACYP2 rs1872328 and WFS1 rs62283056, that have previously been associated with hearing loss in cisplatin-treated patients. Analyses were performed to investigate the association of these variants with ototoxicity in this cohort of adult patients with testicular cancer.Results: Pharmacogenomic analyses revealed that ACYP2 rs1872328 was significantly associated with cisplatin-induced ototoxicity [P = 2.83 × 10-3, OR (95% CI):14.7 (2.6-84.2)]. WFS1 rs62283056 was not significantly associated with ototoxicity caused by cisplatin (P = 0.39); however, this variant was associated with hearing loss attributable to any cause [P = 5.67 × 10-3, OR (95% CI): 3.2 (1.4-7.7)].Conclusions: This study has provided the first evidence for the role of ACYP2 rs1872328 in cisplatin-induced ototoxicity in patients with testicular cancer. These results support the use of this information to guide the development of strategies to prevent cisplatin-induced ototoxicity across cancers. Further, this study has highlighted the importance of phenotypic differences in replication studies and has provided further evidence for the role of WFS1 rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment. Clin Cancer Res; 24(8); 1866-71. ©2018 AACR.
Highlights
Cisplatin is a chemotherapeutic agent that is integral to the treatment of many cancers [1]; the development of ototoxicity is a significant limitation of this therapy [2]
WFS1 rs62283056 was not significantly associated with ototoxicity caused by cisplatin (P 1⁄4 0.39); this variant was associated with hearing loss attributable to any cause [P 1⁄4 5.67 Â 10À3, odds ratio (OR): 3.2 (1.4–7.7)]
This study has highlighted the importance of phenotypic differences in replication studies and has provided further evidence for the role of WFS1 rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment
Summary
Cisplatin is a chemotherapeutic agent that is integral to the treatment of many cancers [1]; the development of ototoxicity is a significant limitation of this therapy [2]. It is estimated that the lifetime costs per patient associated with this adverse drug reaction (ADR) range from $300,000 in adults to over $1,000,000 in children [3]. Clinical variables such as age and dose of cisplatin have been shown to contribute to the development of cisplatin-induced ototoxicity (CIO), there is a large body of evidence showing that genetic variation plays an important role in the development of this ADR [4, 5]. The first GWAS identified a significant association with a genetic variant (rs1872328) in ACYP2 and CIO in pediatric embryonal
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