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

BMC Cancer

Research Article

Takayuki Yoshino¹  Atsushi Ohtsu¹  Toshihiko Doi¹  Yasuhiro Matsumura²  Jun-ichi Sawada³  Hiromi Sakamoto⁴  Teruhiko Yoshida⁴  Misuzu Okuyama⁴  Yoko Odaka⁴  Nahoko Kaniwa⁵  Kimie Sai⁵  Yoshiro Saito⁵  Tetsuya Hamaguchi⁶  Yasuhiro Shimada⁶  Kuniaki Shirao⁶  Hiro Takahashi⁷  Anna Takahashi⁸ 

[1] Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, 277-8577, Kashiwa, Chiba, Japan;Division of Developmental Therapeutics, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, 277-8577, Kashiwa, Chiba, Japan;Division of Functional Biochemistry and Genomics, National Institute of Health Sciences, 1-18-1 Kamiyoga, 158-8501, Setagaya-ku, Tokyo, Japan;Present address: Pharmaceutical and Medical Devices Agency, Shinkasumigaseki-building, 3-3-2 Kasumigaseki, 100-0013, Chiyoda-ku, Tokyo, Japan;Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, 104-0045, Chuo-ku, Tokyo, Japan;Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, 158-8501, Setagaya-ku, Tokyo, Japan;Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, 104-0045, Chuo-ku, Tokyo, Japan;Graduate School of Horticulture, Chiba University, 648 Matsudo, 271-8510, Matsudo, Chiba, Japan;Plant Biology Research Center, Chubu University, Matsumoto-cho 1200, 487-8501, Kasugai, Aichi, Japan;Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, 104-0045, Chuo-ku, Tokyo, Japan;Plant Biology Research Center, Chubu University, Matsumoto-cho 1200, 487-8501, Kasugai, Aichi, Japan;

关键词: Single nucleotide polymorphisms;    Bioinformatics;    Gastric cancer;    Genome-wide association study;    Fluoropyrimidine];   

DOI  :  10.1186/s12885-015-1721-z

 received in 2015-04-17, accepted in 2015-10-08,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundVariability 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.MethodsWe 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.ResultsWe 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.ConclusionsThese 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.

【 授权许可】

CC BY   
© Takahashi et al. 2015