Further Investigation of the Role of <i>ACYP2</i> and <i>WFS1</i> Pharmacogenomic Variants in the Development of Cisplatin-Induced Ototoxicity in Testicular Cancer Patients.

Abstract

<b>Purpose:</b> 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 <i>ACYP2</i> and <i>WFS1</i> 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.<b>Experimental Design:</b> Extensive clinical and demographic data were collected for 229 patients with testicular cancer treated with cisplatin. Patients were genotyped for two variants, <i>ACYP2</i> rs1872328 and <i>WFS1</i> 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.<b>Results:</b> Pharmacogenomic analyses revealed that <i>ACYP2</i> rs1872328 was significantly associated with cisplatin-induced ototoxicity [<i>P</i> = 2.83 × 10^-3, OR (95% CI):14.7 (2.6-84.2)]. <i>WFS1</i> rs62283056 was not significantly associated with ototoxicity caused by cisplatin (<i>P</i> = 0.39); however, this variant was associated with hearing loss attributable to any cause [<i>P</i> = 5.67 × 10^-3, OR (95% CI): 3.2 (1.4-7.7)].<b>Conclusions:</b> This study has provided the first evidence for the role of <i>ACYP2</i> 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 <i>WFS1</i> rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment. <i>Clin Cancer Res; 24(8); 1866-71. ©2018 AACR</i>.