Abstract
Background: Nephrotoxicity is a notable adverse effect in cisplatin treated patients characterized by tubular injury and/or increased serum creatinine (SCr) with incidence varying from 20 to 70%. Pharmacogenomics has been shown to identify strongly predictive genetic markers to help determine which patients are more likely to experience, for example, a serious adverse drug reaction or receive optimal benefit through enhanced efficacy. Genetic variations have been reported to influence the risk of cisplatin nephrotoxicity; however, a comprehensive overview is lacking.Methods: A systematic review was performed using Pubmed, Embase and Web of Science on clinical studies that used cisplatin-based chemotherapy as treatment, had available genotyping data, and evaluated nephrotoxicity as an outcome. The quality of reporting was assessed using the STrengthening the REporting of Genetic Association Studies (STREGA) checklist.Results: Twenty-eight eligible studies were included; all were candidate gene studies. Over 300 SNPs across 135 genes were studied; 29 SNPs in 14 genes were significantly associated with cisplatin-induced nephrotoxicity. A variation in SLC22A2 rs316019, a gene involved in platinum uptake by the kidney, was associated with different measures of nephrotoxicity in four independent studies. Further, variants of ERCC1 (rs11615 and rs3212986) and ERCC2 (rs13181), two genes involved in DNA repair, were found to be positively associated with increased risks of nephrotoxicity in two independent studies.Conclusion: Three genes consistently associated with cisplatin-induced nephrotoxicity. Further research is needed to assess the biological mechanism and the clinical value of modifying treatment based on SLCC22A2 and ERCC1/2 genotypes.
Highlights
Platinum-based chemotherapeutics, such as cisplatin, carboplatin, and oxaliplatin are among the most widely used antineoplastics for the treatment of solid tumors
Over 300 SNPs across 135 genes were studied; 29 SNPs in 14 genes were significantly associated with cisplatin-induced nephrotoxicity
Variants of ERCC1 and ERCC2, two genes involved in DNA repair, were found to be positively associated with increased risks of nephrotoxicity in two independent studies
Summary
Platinum-based chemotherapeutics, such as cisplatin, carboplatin, and oxaliplatin are among the most widely used antineoplastics for the treatment of solid tumors. Despite its benefit in cancer therapy, cisplatin is known for its adverse reactions, such as ototoxicity, neurotoxicity, emesis and nephrotoxicity (Percie du Sert et al, 2011; Wensing and Ciarimboli, 2013; Dasari and Tchounwou, 2014). The efficacy of cisplatin is dose dependent, but the high risk of nephrotoxicity frequently hinders the use of higher doses to maximize its antineoplastic effects (Schellens et al, 2001; Hanigan and Devarajan, 2003). Longterm platinum retention can be found in the plasma of cancer patients even 20 years after discontinuation of cisplatin-based chemotherapy (Gietema et al, 2000; Hjelle et al, 2015), raising concerns about the long-term nephrotoxicity risks over time. Genetic variations have been reported to influence the risk of cisplatin nephrotoxicity; a comprehensive overview is lacking
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