title: Genetic variations in multiple drug action pathways and survival in advanced stage non-small cell lung cancer treated with chemotherapy.
abstract: OBJECTIVE
  Variations in genes related to biological activity of anticancer drugs could influence treatment responses and lung cancer prognosis. Genetic variants in four biological pathways, that is, glutathione metabolism, DNA repair, cell cycle, and epidermal growth factor receptor (EGFR), were systematically investigated to examine their association with survival in advanced stage non-small cell lung cancer (NSCLC) treated with chemotherapy.
  
  
  METHODS
  A total of 894 tagging single-nucleotide polymorphisms (SNP) in 70 genes from the four pathways were genotyped and analyzed in a 1,076-patient cohort. Association with overall survival was analyzed at SNP and whole-gene levels within all patients and major chemotherapy agent combination groups.
  
  
  RESULTS
  A poorer overall survival was observed in patients with genetic variations in GSS (glutathione pathway) and MAP3K1 (EGFR pathway; HR = 1.45; 95% CI = 1.20-1.77 and HR = 1.25; 95% CI = 1.05-1.50, respectively). In the stratified analysis on patients receiving platinum plus taxane treatment, we observed a hazardous effect on overall survival by the MAP3K1 variant (HR = 1.38; 95% CI = 1.11-1.72) and a protective effect by RAF1 (HR = 0.64; 95% CI = 0.50-0.82) in the EGFR pathway. In patients receiving platinum plus gemcitabine treatment, RAF1 and GPX5 (glutathione pathway) genetic variations showed protective effects on survival (HR = 0.54; 95% CI = 0.38-0.77; HR = 0.67; 95% CI = 0.52-0.85, respectively); in contrast, NRAS (EGFR pathway) and GPX7 (glutathione pathway) variations showed hazardous effects on overall survival (HR = 1.91; 95% CI = 1.30-2.80; HR = 1.83; 95% CI = 1.27-2.63, respectively). All genes that harbored these significant SNPs remained significant by whole-gene analysis.
  
  
  CONCLUSIONS
  Common genetic variations in genes of EGFR and glutathione pathways may be associated with overall survival among patients with advanced stage NSCLC treated with platinum, taxane, and/or gemicitabine combinations.
authors.affiliation: Department of Health Sciences Research, Rochester, Minnesota, USA.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Li
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Marie C
authors.initials: MC
authors.lastname: Aubry
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wampfler
authors.forename: Gary A
authors.initials: GA
authors.lastname: Croghan
authors.forename: Cassandra
authors.initials: C
authors.lastname: Johnson
authors.forename: Danli
authors.initials: D
authors.lastname: Wu
authors.forename: Jeremiah A
authors.initials: JA
authors.lastname: Aakre
authors.forename: Julian
authors.initials: J
authors.lastname: Molina
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D002453:Cell Cycle / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D010984:Platinum / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D043823:Taxoids; D003841:Deoxycytidine; C080625:taxane; D010984:Platinum; D005979:Glutathione Peroxidase; C080439:selenium-independent glutathione peroxidase; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf; D005978:Glutathione; D000093542:Gemcitabine