Gemcitabine metabolic pathway genetic polymorphisms and response in patients with non-small cell lung cancer

Liang Li, Daniel J. Schaid, Brooke L. Fridley, Krishna R. Kalari, Gregory D. Jenkins, Ryan P. Abo, Anthony Batzler, Irene Moon, Linda Pelleymounter, Bruce W. Eckloff, Eric D. Wieben, Zhifu Sun, Ping Yang, Liewei Wang

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Background and Objective: Gemcitabine is widely used to treat non-small cell lung cancer (NSCLC). The aim of this study was to assess the pharmacogenomic effects of the entire gemcitabine metabolic pathway, we genotyped single nucleotide polymorphisms (SNPs) within the 17 pathway genes using DNA samples from patients with NSCLC treated with gemcitabine to determine the effect of genetic variants within gemcitabine pathway genes on overall survival (OS) of patients with NSCLC after treatment of gemcitabine. Methods: Eight of the 17 pathway genes were resequenced with DNA samples from Coriell lymphoblastoid cell lines (LCLs) using Sanger sequencing for all exons, exon-intron junctions, and 5′-, 3′-UTRs. A total of 107 tagging SNPs were selected on the basis of the resequencing data for the eight genes and on HapMap data for the remaining nine genes, followed by successful genotyping of 394 NSCLC patient DNA samples. Association of SNPs/haplotypes with OS was performed using the Cox regression model, followed by functional studies performed with LCLs and NSCLC cell lines. Results: Five SNPs in four genes (CDA, NT5C2, RRM1, and SLC29A1) showed associations with OS of those patients with NSCLC, as well as nine haplotypes in four genes (RRM1, RRM2, SLC28A3, and SLC29A1) with a P value of less than 0.05. Genotype imputation using the LCLs was performed for a region of 200 kb surrounding those SNPs, followed by association studies with gemcitabine cytotoxicity. Functional studies demonstrated that downregulation of SLC29A1, NT5C2, and RRM1 in NSCLC cell lines altered cell susceptibility to gemcitabine. Conclusion: These studies help in identifying biomarkers to predict gemcitabine response in NSCLC, a step toward the individualized chemotherapy of lung cancer.

Original languageEnglish (US)
Pages (from-to)105-116
Number of pages12
JournalPharmacogenetics and genomics
Volume22
Issue number2
DOIs
StatePublished - Feb 2012

Keywords

  • gemcitabine
  • lymphoblastoid cell line
  • metabolic pathway
  • non-small cell lung cancer
  • pharmacogenomics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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