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
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Published in |
BMC Cancer, October 2015
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DOI | 10.1186/s12885-015-1721-z |
Pubmed ID | |
Authors |
Hiro Takahashi, Nahoko Kaniwa, Yoshiro Saito, Kimie Sai, Tetsuya Hamaguchi, Kuniaki Shirao, Yasuhiro Shimada, Yasuhiro Matsumura, Atsushi Ohtsu, Takayuki Yoshino, Toshihiko Doi, Anna Takahashi, Yoko Odaka, Misuzu Okuyama, Jun-ichi Sawada, Hiromi Sakamoto, Teruhiko Yoshida |
Abstract |
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. 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. 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. 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. |
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Geographical breakdown
Country | Count | As % |
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Unknown | 32 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 5 | 16% |
Student > Bachelor | 4 | 13% |
Student > Doctoral Student | 4 | 13% |
Student > Master | 4 | 13% |
Researcher | 4 | 13% |
Other | 5 | 16% |
Unknown | 6 | 19% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 9 | 28% |
Biochemistry, Genetics and Molecular Biology | 5 | 16% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 6% |
Agricultural and Biological Sciences | 2 | 6% |
Psychology | 2 | 6% |
Other | 6 | 19% |
Unknown | 6 | 19% |