Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression.
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.
Cha
Pei-Chieng
PC
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Mushiroda
Taisei
T
Zembutsu
Hitoshi
H
Harada
Hiromasa
H
Shinoda
Noriyuki
N
Kawamoto
Shunji
S
Shimoyama
Rai
R
Nishidate
Toshihiko
T
Furuhata
Tomohisa
T
Sasaki
Kazuaki
K
Hirata
Koichi
K
Nakamura
Yusuke
Y
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000235:genetics*; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D012189:Retrospective Studies
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D000077146:Irinotecan; D002166:Camptothecin