title: Application of a combination of a knowledge-based algorithm and 2-stage screening to hypothesis-free genomic data on irinotecan-treated patients for identification of a candidate single nucleotide polymorphism related to an adverse effect.
abstract: Interindividual variation in a drug response among patients is known to cause serious problems in medicine. Genomic information has been proposed as the basis for "personalized" health care. The genome-wide association study (GWAS) is a powerful technique for examining single nucleotide polymorphisms (SNPs) and their relationship with drug response variation; however, when using only GWAS, it often happens that no useful SNPs are identified due to multiple testing problems. Therefore, in a previous study, we proposed a combined method consisting of a knowledge-based algorithm, 2 stages of screening, and a permutation test for identifying SNPs. In the present study, we applied this method to a pharmacogenomics study where 109,365 SNPs were genotyped using Illumina Human-1 BeadChip in 168 cancer patients treated with irinotecan chemotherapy. We identified the SNP rs9351963 in potassium voltage-gated channel subfamily KQT member 5 (KCNQ5) as a candidate factor related to incidence of irinotecan-induced diarrhea. The p value for rs9351963 was 3.31×10-5 in Fisher's exact test and 0.0289 in the permutation test (when multiple testing problems were corrected). Additionally, rs9351963 was clearly superior to the clinical parameters and the model involving rs9351963 showed sensitivity of 77.8% and specificity of 57.6% in the evaluation by means of logistic regression. Recent studies showed that KCNQ4 and KCNQ5 genes encode members of the M channel expressed in gastrointestinal smooth muscle and suggested that these genes are associated with irritable bowel syndrome and similar peristalsis diseases. These results suggest that rs9351963 in KCNQ5 is a possible predictive factor of incidence of diarrhea in cancer patients treated with irinotecan chemotherapy and for selecting chemotherapy regimens, such as irinotecan alone or a combination of irinotecan with a KCNQ5 opener. Nonetheless, clinical importance of rs9351963 should be further elucidated.
authors.affiliation: Graduate School of Horticulture, Chiba University, Matsudo, Chiba, Japan; Plant Biology Research Center, Chubu University, Kasugai, Aichi, Japan; Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiro
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Sai
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.affiliation: Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Division of Medicinal Safety Science, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Okuda
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan; Faculty of Horticulture, Chiba University, Matsudo, Chiba, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Ichinohe
authors.affiliation: Plant Biology Research Center, Chubu University, Kasugai, Aichi, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan; Faculty of Horticulture, Chiba University, Matsudo, Chiba, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Doi
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Odaka
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Misuzu
authors.initials: M
authors.lastname: Okuyama
authors.affiliation: National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.affiliation: Division of Functional Biochemistry and Genomics, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.affiliation: Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
mesh_terms: D000328:Adult; D000465:Algorithms; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003967:Diarrhea / Q000139:chemically induced* / Q000235:genetics; D005260:Female; D015894:Genome, Human; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D000077146:Irinotecan; D051656:KCNQ Potassium Channels / Q000235:genetics*; D051188:Knowledge Bases; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051656:KCNQ Potassium Channels; C412231:KCNQ5 protein, human; D000077146:Irinotecan; D002166:Camptothecin