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Identification of a candidate single-nucleotide polymorphism related to chemotherapeutic response through a combination of knowledge-based algorithm and hypothesis-free genomic data.

Abstract
Inter-individual variations in drug responses among patients are known to cause serious problems in medicine. Genome-wide association study (GWAS) is powerful for examining single-nucleotide polymorphisms (SNPs) and their relationships with drug response variations. However, no significant SNP has been identified using GWAS due to multiple testing problems. Therefore, we propose a combination method consisting of knowledge-based algorithm, two stages of screening, and permutation test for identifying SNPs in the present study. We applied this method to a genome-wide pharmacogenomics study for which 109,365 SNPs had been genotyped using Illumina Human-1 BeadChip for 119 gastric cancer patients treated with fluoropyrimidine. We identified rs2293347 in epidermal growth factor receptor (EGFR) is as a candidate SNP related to chemotherapeutic response. The p value for the rs2293347 was 2.19 × 10(-5) for Fisher's exact test, and the p value was 0.00360 for the permutation test (multiple testing problems are corrected). Additionally, rs2293347 was clearly superior to clinical parameters and showed a sensitivity value of 55.0% and specificity value of 94.4% in the evaluation by using multiple regression models. Recent studies have shown that combination chemotherapy of fluoropyrimidine and EGFR-targeting agents is effective for gastric cancer patients highly expressing EGFR. These results suggest that rs2293347 is a potential predictive factor for selecting chemotherapies, such as fluoropyrimidine alone or combination chemotherapies.
AuthorsHiro Takahashi, Nahoko Kaniwa, Yoshiro Saito, Kimie Sai, Tetsuya Hamaguchi, Kuniaki Shirao, Yasuhiro Shimada, Yasuhiro Matsumura, Atsushi Ohtsu, Takayuki Yoshino, Anna Takahashi, Yoko Odaka, Misuzu Okuyama, Jun-ichi Sawada, Hiromi Sakamoto, Teruhiko Yoshida
JournalJournal of bioscience and bioengineering (J Biosci Bioeng) Vol. 116 Issue 6 Pg. 768-73 (Dec 2013) ISSN: 1347-4421 [Electronic] Japan
PMID23816762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Antimetabolites, Antineoplastic
  • ErbB Receptors
  • Fluorouracil
Topics
  • Algorithms
  • Antimetabolites, Antineoplastic (pharmacology)
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Colonic Neoplasms (drug therapy, genetics)
  • Computational Biology
  • ErbB Receptors (genetics)
  • Female
  • Fluorouracil (pharmacology)
  • Genome-Wide Association Study
  • Genomics
  • Humans
  • Male
  • Pharmacogenetics
  • Polymorphism, Single Nucleotide
  • Regression Analysis
  • Stomach Neoplasms (drug therapy, genetics)

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