This study has identified a novel association between protein-coding variation in SLC16A5 and cisplatin-induced ototoxic effects. These findings have provided insight into the molecular mechanisms of this adverse drug reaction in adult patients with germ cell testicular cancer. Given that previous studies have shown that cimetidine, an SLC16A5-inhibitor, prevents murine cisplatin-induced ototoxic effects, the findings from this study have important implications for otoprotectant strategies in humans.

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 and 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. Extensive clinical and demographic data were collected for 229 patients with testicular cancer treated with cisplatin. Patients were genotyped for two variants, rs1872328 and 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. Pharmacogenomic analyses revealed that rs1872328 was significantly associated with cisplatin-induced ototoxicity [ = 2.83 × 10, OR (95% CI):14.7 (2.6-84.2)]. rs62283056 was not significantly associated with ototoxicity caused by cisplatin ( = 0.39); however, this variant was associated with hearing loss attributable to any cause [ = 5.67 × 10, OR (95% CI): 3.2 (1.4-7.7)]. This study has provided the first evidence for the role of 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 rs62283056 in susceptibility to hearing loss, which may be worsened by cisplatin treatment. .

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<div>Abstract<p><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.</p><p><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.</p><p><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)].</p><p><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>.</p></div>

<div>Abstract<p><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.</p><p><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.</p><p><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)].</p><p><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>.</p></div>