title: A novel system for predicting the toxicity of irinotecan based on statistical pattern recognition with UGT1A genotypes.
abstract: To predict precisely severe toxicity of irinotecan, we evaluated the association of UGT1A variants, haplotypes and the combination of UGT1A genotypes to severe toxicity of irinotecan. UGT1A1*6 (211G>A), UGT1A1*28 (TA6>TA7), UGT1A1*60 (-3279T>G), UGT1A7 (387T>G), UGT1A7 (622T>C), and UGT1A9*1b (-118T9>T10, also named *22) were genotyped in 123 patients with metastatic colorectal cancer who had received irinotecan-based chemotherapy. Among the 123 patients, 73 were enrolled in either of two phase II studies of the FOLFIRI (leucovorin, 5-fluorouracil and irinotecan) regimen; these patients constituted the training population, which was used to construct the predicting system. The other 50 patients constituted the validation population; these 50 patients either had participated in a phase II study of irinotecan/5'-deoxy-5-fluorouridine or were among consecutive patients who received FOLFIRI therapy. This prediction system used sequential forward floating selection based on statistical pattern recognition using UGT1A genotypes, gender and age. Several UGT1A genotypes [UGT1A1*6, UGT1A7 (387T>G), UGT1A7 (622T>C) and UGT1A9*1b] were associated with the irinotecan toxicity. Among the haplotypes, haplotype-I (UGT1A1: -3279T, TA6, 211G; UGT1A7: 387T, 622T; UGT1A9: T10) and haplotype-II (UGT1A1: -3279T, TA6, 211A; UGT1A7: 387G, 622C; UGT1A9: T9) were also associated with irinotecan toxicity. Furthermore, our new system for predicting the risk of irinotecan toxicity was 83.9% accurate with the training population and 72.1% accurate with the validation population. Our novel prediction system using statistical pattern recognition depend on genotypes in UGT1A, age and gender; moreover, it showed high predictive performance even though the treatment regimens differed among the training and validation patients.
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Ryouichi
authors.initials: R
authors.lastname: Tsunedomi
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Hazama
authors.affiliation: Department of Computer Science and Systems Engineering, Faculty of Engineering, Yamaguchi University, Yamaguchi 755-8611, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Clinical Laboratory, Yamaguchi University Hospital, Yamaguchi 755-8505, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Okayama
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kanekiyo
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inoue
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Yoshino
authors.affiliation: Department of Clinical Laboratory, Yamaguchi University Hospital, Yamaguchi 755-8505, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Department of Clinical Laboratory, Yamaguchi University Hospital, Yamaguchi 755-8505, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suehiro
authors.affiliation: Translational Research and Clinical Trial Center, Hokkaido University Hospital, Sapporo 060-8638, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Oba
authors.affiliation: Unit of Cancer Center, Aichi Medical University, Nagakute 480-1195, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Mishima
authors.affiliation: Tokai Central Hospital, Aichi 504-8601, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Sakamoto
authors.affiliation: Department of Computer Science and Systems Engineering, Faculty of Engineering, Yamaguchi University, Yamaguchi 755-8611, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Hamamoto
authors.affiliation: Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Oka
mesh_terms: D000368:Aged; D000465:Algorithms; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D020641:Polymorphism, Single Nucleotide; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme