Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression

Abstract

Irinotecan is an anti-neoplastic agent that is widely used for treating colorectal and lung cancers, but often causes toxicities such as severe myelosuppression and diarrhea. In this study, we performed a two-stage case-control association study for irinotecan-induced severe myelosuppression (grades 3 and 4). In the first stage, 23 patients who developed severe myelosuppression and 58 patients who did not develop any toxicity were examined for 170 single nucleotide polymorphisms (SNPs) in 14 genes involved in the metabolism and transport of irinotecan. A total of five SNPs were identified to show the possible association with severe myelosuppression (P(Fisher)<0.01) and were further examined in 7 cases and 20 controls in the second stage of the study. An intronic SNP, rs2622604, in ABCG2 showed P(Fisher)=0.0419 in the second stage and indicated a significant association with severe myelosuppression in the combined study (P(Fisher)=0.000237; P(Corrected)=0.036). Although only limited subjects were investigated, our results suggested that a genetic polymorphism in ABCG2 might alter the transport activity for the drug and elevate the systemic circulation level of irinotecan, leading to severe myelosuppression.

Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

“…Specifically, in a previous clinical study the rs2622604 SNP was associated with irinotecaninduced myelosuppression, proposed to occur consequently to higher levels of the drug in the systemic circulation [40]. In addition, this SNP has been associated with increased plasma exposure to erlotinib [41] and higher risk for the development of gefitinib [42] and sunitinib [43] induced toxicity/ adverse events.…”

A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor

“…ABCG2 is a transporter protein involved in the transit of drugs in the small intestine [23]. SNPs of ABCG2 have been postulated to be associated with toxicities including diarrhea and myelosuppression [24]. Pyrosequencing evaluation of the ABCG2 gene was conducted to evaluate for the SNP at codon 421 for a C >A transversion (as this polymorphism has been linked to diarrhea following administration of certain antineoplastic agents, including epidermal growth factor receptor [EGFR] tyrosine kinase inhibitors) [25,26].…”

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

“…An example of contradictory findings is irinotecan, where, the ABCG2 c.421C>A polymorphism has been reported to be associated with an increased incidence of neutropenia in a Japanese cohort of cancer patients [118]. Another study reported an association between an intronic polymorphism and severe irinotecan induced myelosuppression [119]. In contrast, two further studies did not find any association with irinotecan disposition [120,121], but Han and coworkers found an association with response rate and progression-free survival [121].…”