Influence of genetic variation in COMT on cisplatin-induced nephrotoxicity in cancer patients

Background Cisplatin is a widely used chemotherapeutic agent for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin acute kidney injury (AKI) occurs. A recent case report suggested single nucleotide polymorphisms (SNPs) in the COMT gene might be associated with increased cisplatin-induced nephrotoxicity (de Jong et al., BJCP, 2017). Here, we assessed the association of 3 SNPs in this gene with cisplatin-induced nephrotoxicity in our patient population. Methods Whole blood samples and serum creatinine concentrations (Scr) of 556 patients who received cisplatin between 2005-2019 were available. The 1947 G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316) and c.616 – 367 C>T (rs9332377) SNPs were associated with AKI (CTCAE v4.03) using Fisher’s exact test and difference in Scr up to 2 weeks prior to and up to 6 weeks after cisplatin treatment was described. Results Median Scr at baseline was 70 μmol/l (inter quartile range (IQR) 59-81). Up to six weeks after the start of cisplatin treatment the median increased to 81 μmol/l (IQR 69-96). The presence of a variant of c.615 + 310C>T was associated with an increased occurrence of AKI ≥ grade 3 toxicity in patients carrying a homozygous variant (Var) compared to wildtype (WT) patients. AKI grade ≥ 3 occurred in 4 out of 31 (13%) homozygous variant patients against 6 out of 317 (2%) patients carrying wildtype alleles (p = 0.005) after correction for age in a multivariable model. Dehydration occurred in 14 of the 16 patients with AKI grade 3 (3 of 4 WT, 6 of 6 HT and 5 of 6 Var) and likely is a confounding factor. The remaining SNPs were not significantly associated with AKI or difference in Scr. Conclusions This study showed that variation in COMT c.615 + 310 C>T (rs4646316) potentially affects the development of AKI grade ≥3, although these results appear to be confounded by dehydration. Therefore, the value of this finding for daily practice is currently unclear and needs to be explored in a prospective setting. Legal entity responsible for the study R.H.J. Mathijssen. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.