Rapid and sensitive detection of UGT1A1 polymorphisms associated with irinotecan toxicity by a novel DNA microarray

Abstract

Recent developments in the field of human genomics have greatly enhanced the potential for precision and personalized medicine. We have developed a novel DNA microarray, using a 3‐mm square chip coated with diamond‐like carbon to enhance the signal‐to‐background ratio, for use as an in vitro diagnostic tool in precision medicine. To verify the genotyping effectiveness of this newly developed DNA microarray we examined UDP‐glucuronosyltransferase 1A1 (UGT1A1) polymorphisms in DNA extracted from patients with metastatic colorectal cancer. It is established that the polymorphisms of UGT1A1*28 and UGT1A1*6 are significantly associated with severe toxicity induced by the anti‐cancer drug irinotecan. For each sample, the results obtained with the novel microarray platform were compared with those obtained using other, more established, methods, including direct sequencing and the Invader assay. The polymorphisms tested included a single nucleotide substitution (UGT1A1*6) and a TA‐repeat polymorphism (UGT1A1*28), both of which were detected simultaneously and accurately using our method. Moreover, our method required 1.5‐fold less time to assay and 20‐fold less sample than those required by the Invader assay. In summary, our newly developed DNA microarray is more practical than established methods, and is at least as accurate; this will increase the efficiency of polymorphism detection prior to diagnosis and the commencement of treatment, and can feasibly be applied in precision medicine.

Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors

“…Because of such changes in expression and/or activity, polymorphic UGT variants may cause higher plasma concentrations of (toxic) metabolites or parent compounds, resulting in chemical-induced toxicity. For example, UGT1A1 polymorphism is associated with irinotecan toxicity, while UGT2B7 polymorphism can affect plasma concentrations of valproic acid (Tsunedomi et al 2017 ; Wang et al 2018b ). For other isoforms, comparable impact of UGT polymorphisms on internal drug concentrations has been observed (Stingl et al 2014 ).…”

Next Generation Risk Assessment of Chemicals

“…Because of such changes in expression and/or activity, polymorphic UGT variants may cause higher plasma concentrations of (toxic) metabolites or parent compounds, resulting in chemical-induced toxicity. For example, UGT1A1 polymorphism is associated with irinotecan toxicity, while UGT2B7 polymorphism can affect plasma concentrations of valproic acid (Tsunedomi et al 2017;Wang et al 2018b). For other isoforms, comparable impact of UGT polymorphisms on internal drug concentrations has been observed (Stingl et al 2014).…”