Association Between SLC16A5 Genetic Variation and Cisplatin-Induced Ototoxic Effects in Adult Patients With Testicular Cancer

Abstract

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.

Pharmacogenomics of Cisplatin‐Induced Ototoxicity: Successes, Shortcomings, and Future Avenues of Research

“…demonstrated that TPMT expression is induced by cisplatin in embryonic stem cells, providing further evidence for this drug–gene relationship. The TPMT and COMT associations have been investigated in multiple cohorts, and although some studies have replicated these associations, others were unable to confirm these findings ( Table and Table ). These conflicting results may in part be attributed to the heterogeneity of the cohorts under investigation, as discussed in more detail in the section “Confounding Factors.” Of note, when excluding cohorts of patients who all received cranial irradiation or that included adult patients, the findings from all but one study showed that TPMT rs12201199 was either significantly more frequent in cases when compared with controls, or trended toward significance ( P = 0.07) .…”

“…a Effect allele direction with “+” associated with increased risk of CIO “−” associated with decreased risk of CIO. b Analyses were repeated excluding cohorts of patients who all received cranial irradiation or which included adult patients …”

“…However, there has been an inability to consistently replicate these candidate gene findings, as highlighted for six of the seven CIO candidate genes that are recorded on the curated pharmacogenomic database, PharmGKB ( GSTM1 , GSTT1 , LRP2 , XPC , SLC22A2 , and SLC31A1 ) . The most promising evidence that is summarized on PharmGKB was available for rs1695 in GSTP1 , for which significant associations are recorded from two studies . Given the potential relevance of this gene to CIO, we further mined the literature to identify publications that may have not been captured by the PharmGKB curation process.…”

“…Expanding on the ADME panel approach used by Ross et al ., a second study was performed by the researchers at the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) in a cohort of adult patients with testicular cancer . This study examined 7,907 pharmacogenetic variants and also applied a two‐stage study design, whereby variants with P < 5.0 × 10 −5 in the discovery cohort were investigated for association with CIO in the replication cohort.…”

Clinical and Functional Relevance of the Monocarboxylate Transporter Family in Disease Pathophysiology and Drug Therapy

“…In this way, inhibition of MCT4, especially by lipophilic statins, is proposed to be involved in statin‐induced cytotoxicity and muscle pain 91. A very recent study demonstrates a novel association between a genetic variant in the SLC16A5 gene, encoding for MCT6, and cisplatin‐induced hearing loss 92. The common genetic synonymous variant, rs4788863, in the coding region of SLC16A5 , which is predicted to alter the rate of codon usage, exerted a protective effect on cisplatin‐induced ototoxicity in patients with testicular cancer.…”