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. 2015 Oct 16;15:718. doi: 10.1186/s12885-015-1721-z.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A3 / genetics*
  • Computational Biology / methods
  • Drug Resistance, Neoplasm / genetics
  • Drug Therapy
  • ErbB Receptors / genetics*
  • Female
  • Fluorouracil / administration & dosage
  • Fluorouracil / adverse effects
  • Genome-Wide Association Study
  • Humans
  • Japan
  • Male
  • Mutation
  • Polymorphism, Single Nucleotide
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology

Substances

  • EGFR protein, human
  • ErbB Receptors
  • Annexin A3
  • Fluorouracil