| Popis: |
The renin-angiotensin system (RAS) plays a role in cell proliferation, immunoinflammatory response and angiogenesis in lung cancer. We sought to study the association of functional genetic polymorphisms in RAS, hypoxia and angiogenesis with NSCLC prognosis. Genotyping for ACE, ACE2, AGT, AGTR1, AGTR2, MME, CMA1, MAS1, HIF1A, VEGFA, KDR, PGF, FLT1 was performed using MassARRAY iPLEX Gold in NSCLC patients (IIIA-IVB) from Coimbra University Hospital (n=168, discovery set), and in clinical/pathological-matched patients from Thoraxklinik (n=200, validation set). Multivariate analysis revealed that ACE2 rs908004 homozygous GG/CC and AGTR1 rs380400 GG/AA, were significantly associated with time-to-disease progression (HR=3.2, 95%CI=1.5-6.7, p=0.003 and HR=1.9, 95%CI=1.2-3.0, p=0.010, respectively). MME rs701109 C allele carriers had protection for disease progression (HR=0.4, 95%CI=0.2-0.8, p=0.005). Univariate analysis showed that VEGF rs25648 homozygous was associated with progression free survival (PFS) [HR=1.7 (95% CI 1.0-2,6), p=0.030]. There was a significant association of KDR rs1870377 homozygous TT/AA with overall survival (OS) [HR=1.9 (95% CI 1.1-3.2), p=0.014] and T allele carriers of ACE rs4316 were associated with longer OS [HR=0.5 (95% CI 0.3-0.9), p=0.013]. A subgroup analysis in EGFR wild-type patients (n=175) from the validation set, showed that MME rs701109 homozygous T and VEGF rs25648 homozygous T were associated with shorter PFS (HR=1.4, 95%CI=1.0-2.0, p=0.041; HR=2.8, 95%CI=1.1-6.9, p=0.026). We conclude that functional polymorphisms of MME and VEGF may add predictive value for clinical management of NSCLC risk of progression. |
