title: Gemcitabine metabolic pathway genetic polymorphisms and response in patients with non-small cell lung cancer.
abstract: 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.
  
  
  CONCLUSIONS
  These studies help in identifying biomarkers to predict gemcitabine response in NSCLC, a step toward the individualized chemotherapy of lung cancer.
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Kalari
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Jenkins
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Abo
authors.forename: Anthony
authors.initials: A
authors.lastname: Batzler
authors.forename: Irene
authors.initials: I
authors.lastname: Moon
authors.forename: Linda
authors.initials: L
authors.lastname: Pelleymounter
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Eckloff
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieben
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005838:Genotype; D060148:HapMap Project; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D011110:Polymorphism, Genetic; D015398:Signal Transduction / Q000235:genetics*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D003841:Deoxycytidine; D000093542:Gemcitabine