Abstract
Cisplatin is a chemotherapeutic agent widely used for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin, dose-limiting acute kidney injury (AKI) occurs. Here, we assessed the association of 3 catechol-O-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) with increased cisplatin-induced nephrotoxicity. In total, 551 patients were genotyped for the 1947 G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316), and c.616–367 C>T (rs9332377) polymorphisms. Associations between these variants and AKI grade ≥3 were studied. The presence of a homozygous variant of c.616-367C>T was associated with a decreased occurrence of AKI grade 3 toxicity (p = 0.014, odds ratio (OR) 0.201, 95% confidence interval (CI) (0.047–0.861)). However, we could not exclude the role of dehydration as a potential cause of AKI in 25 of the 27 patients with AKI grade 3, which potentially affected the results substantially. As a result of the low incidence of AKI grade 3 in this dataset, the lack of patients with a COMT variant, and the high number of patients with dehydration, the association between COMT variants and AKI does not seem clinically relevant.
Highlights
Cisplatin is a widely used cytostatic agent that interferes with DNA replication by binding within DNA strands resulting in the inhibition of protein synthesis and DNA replication
In 25 out of 27 patients that had acute kidney injury (AKI) grade 3, dehydration could not be excluded as a potential cause of AKI (Table 3)
We found a significant association b dehydration could not be excluded as a potential cause of AKI
Summary
Cisplatin is a widely used cytostatic agent that interferes with DNA replication by binding within (and between) DNA strands resulting in the inhibition of protein synthesis and DNA replication. Genes 2020, 11, 358 candidate genes, of which two are SNPs in COMT, were genotyped in a young woman who developed severe irreversible cisplatin-induced nephropathy Both COMT polymorphisms were already known to be associated with cisplatin induced ototoxicity [4,5] and were homozygous polymorphic in this patient (c.615 + 310C>T (rs4646316) and c.616-367C>T (rs9332377)) [3]. This theory is supported by data from a mouse model study where cisplatin toxicity was 3- to 6-fold increased when SAM and cisplatin were administered concomitantly, compared to cisplatin administration alone [6] The association between these two COMT polymorphisms and cisplatin-induced nephrotoxicity has not been validated in further clinical research. We studied the association between these three COMT polymorphisms and cisplatin-induced nephrotoxicity in a large cohort of cancer patients in order to assess the clinical relevance of these SNPs and their potential use as predictor in this context
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