title: Functional FLT1 Genetic Variation is a Prognostic Factor for Recurrence in Stage I-III Non-Small-Cell Lung Cancer.
abstract: BACKGROUND
  We propose that single-nucleotide polymorphisms (SNPs) in genes of the vascular endothelial growth factor pathway of angiogenesis will associate with survival in non-small-cell lung cancer (NSCLC) patients.
  
  
  METHODS
  Fifty-three SNPs in vascular endothelial growth factor-pathway genes were genotyped in 150 European stage I-III NSCLC patients and tested for associations with patient survival. Replication was performed in an independent cohort of 142 European stage I-III patients. Reporter gene assays were used to assess the effects of SNPs on transcriptional activity.
  
  
  RESULTS
  In the initial cohort, five SNPs associated (q < 0.05) with relapse-free survival (RFS). The minor alleles of intronic FLT1 SNPs, rs7996030 and rs9582036, associated with reduced RFS (hazard ratio [HR] = 1.67 [95% confidence interval, CI, 1.22-2.29] and HR = 1.51 [95% CI, 1.14-2.01], respectively) and reduced transcriptional activity. The minor alleles of intronic KRAS SNPs, rs12813551 and rs10505980, associated with increased RFS (HR = 0.64 [0.46-0.87] and HR = 0.64 [0.47-0.87], respectively), and the minor allelic variant of rs12813551 also reduced transcriptional activity. Lastly, the minor allele of the intronic KRAS SNP rs10842513 associated with reduced RFS (HR = 1.65 [95% CI, 1.16-2.37]). Analysis of the functional variants suggests they are located in transcriptional enhancer elements. The negative effect of rs9582036 on RFS was confirmed in the replication cohort (HR = 1.69 [0.99-2.89], p = 0.028), and the association was significant in pooled analysis of both cohorts (HR = 1.67 [1.21-2.30], p = 0.0001).
  
  
  CONCLUSIONS
  The functional FLT1 variant rs9582036 is a prognostic determinant of recurrence in stage I-III NSCLC. Its predictive value should be tested in the adjuvant setting of stage I-III NSCLC.
authors.affiliation: *Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina; †Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia; ‡Department of Genetics, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; §Molecular Oncology Laboratory, General University Hospital Research Foundation, Valencia, Spain; ‖Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina; ¶Department of Medicine, University of Chicago, Chicago, Illinois; #Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois; **Department of Thoracic Surgery, and ††Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland; ‡‡Department of Medicine, University of Colorado Cancer Center, Aurora, Colorado; §§Department of Medicine, University of Valencia, Valencia, Spain; ‖‖Department of Oncology, General University Hospital of Valencia, Valencia, Spain; and ¶¶Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Dylan M
authors.initials: DM
authors.lastname: Glubb
authors.forename: Laia
authors.initials: L
authors.lastname: Paré-Brunet
authors.forename: Eloisa
authors.initials: E
authors.lastname: Jantus-Lewintre
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.forename: Daniel
authors.initials: D
authors.lastname: Crona
authors.forename: Amy S
authors.initials: AS
authors.lastname: Etheridge
authors.forename: Osman
authors.initials: O
authors.lastname: Mirza
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Eric L
authors.initials: EL
authors.lastname: Seiser
authors.forename: Witold
authors.initials: W
authors.lastname: Rzyman
authors.forename: Jacek
authors.initials: J
authors.lastname: Jassem
authors.forename: Todd
authors.initials: T
authors.lastname: Auman
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.forename: Carlos
authors.initials: C
authors.lastname: Camps
authors.forename: Rafal
authors.initials: R
authors.lastname: Dziadziuszko
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016019:Survival Analysis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1