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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.

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (p=6.6×10−14) greater metformin-induced in haemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 is the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.