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BackgroundWe 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.MethodsFifty-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.ResultsIn 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).ConclusionsThe 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.

Original publication

DOI

10.1097/jto.0000000000000549

Type

Journal article

Journal

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

Publication Date

07/2015

Volume

10

Pages

1067 - 1075

Addresses

*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.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Neoplasm Recurrence, Local, Vascular Endothelial Growth Factor Receptor-1, Neoplasm Staging, Prognosis, Disease-Free Survival, Survival Analysis, Cohort Studies, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Genetic Variation, Biomarkers, Tumor