title: Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method.
abstract: BACKGROUND
  Variability in drug response between individual patients is a serious concern in medicine. To identify single-nucleotide polymorphisms (SNPs) related to drug response variability, many genome-wide association studies have been conducted.
  
  
  METHODS
  We previously applied a knowledge-based bioinformatic approach to a pharmacogenomics study in which 119 fluoropyrimidine-treated gastric cancer patients were genotyped at 109,365 SNPs using the Illumina Human-1 BeadChip. We identified the SNP rs2293347 in the human epidermal growth factor receptor (EGFR) gene as a novel genetic factor related to chemotherapeutic response. In the present study, we reanalyzed these hypothesis-free genomic data using extended knowledge.
  
  
  RESULTS
  We identified rs2867461 in annexin A3 (ANXA3) gene as another candidate. Using logistic regression, we confirmed that the performance of the rs2867461 + rs2293347 model was superior to those of the single factor models. Furthermore, we propose a novel integrated predictive index (iEA) based on these two polymorphisms in EGFR and ANXA3. The p value for iEA was 1.47 × 10(-8) by Fisher's exact test. Recent studies showed that the mutations in EGFR is associated with high expression of dihydropyrimidine dehydrogenase, which is an inactivating and rate-limiting enzyme for fluoropyrimidine, and suggested that the combination of chemotherapy with fluoropyrimidine and EGFR-targeting agents is effective against EGFR-overexpressing gastric tumors, while ANXA3 overexpression confers resistance to tyrosine kinase inhibitors targeting the EGFR pathway.
  
  
  CONCLUSIONS
  These results suggest that the iEA index or a combination of polymorphisms in EGFR and ANXA3 may serve as predictive factors of drug response, and therefore could be useful for optimal selection of chemotherapy regimens.
authors.affiliation: Graduate School of Horticulture, Chiba University, 648 Matsudo, Matsudo, Chiba, 271-8510, Japan. hiro.takahashi@chiba-u.jp.|Plant Biology Research Center, Chubu University, Matsumoto-cho 1200, Kasugai, Aichi, 487-8501, Japan. hiro.takahashi@chiba-u.jp.|Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. hiro.takahashi@chiba-u.jp.
authors.forename: Hiro
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan. nkaniwa@nihs.go.jp.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan. yoshiro@nihs.go.jp.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan. sai@nihs.go.jp.
authors.forename: Kimie
authors.initials: K
authors.lastname: Sai
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. thamaguc@ncc.go.jp.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. kshirao@oita-u.ac.jp.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. yasuhiro.shimada@gmail.com.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. yhmatsum@east.ncc.go.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. aohtsu@east.ncc.go.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tyoshino@east.ncc.go.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tdoi@east.ncc.go.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Plant Biology Research Center, Chubu University, Matsumoto-cho 1200, Kasugai, Aichi, 487-8501, Japan. tsubasa-new@hotmail.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. yodaka@ncc.go.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Odaka
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. mokuyam@ncc.go.jp.
authors.forename: Misuzu
authors.initials: M
authors.lastname: Okuyama
authors.affiliation: Division of Functional Biochemistry and Genomics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan. sawada@nihs.go.jp.|Present address: Pharmaceutical and Medical Devices Agency, Shinkasumigaseki-building, 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan. sawada@nihs.go.jp.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Sawada
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. hsakamot@ncc.go.jp.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. tyoshida@ncc.go.jp.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
mesh_terms: D017318:Annexin A3 / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004358:Drug Therapy; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors; D017318:Annexin A3; D005472:Fluorouracil