The angiogenesis is an important process in the pathogenesis of malignancies. It is regulated by various growth factors, with the vascular endothelial growth factor (VEGF) playing the central role. The aim of the present study was to evaluate possible associations of functional VEGF −2578C>A, −634G>C, and +936C>T polymorphisms with the risk for occurrence and progression of non-small cell lung cancer (NSCLC) in patients living in Republic of Belarus. Materials and Methods: A total of 202 patients (147 males and 55 females) diagnosed as having the NSCLC. The control group consisted of 336 individuals (245 males and 91 females) without an oncopathology. The total DNA was isolated from peripheral blood. We investigated the single nucleotide polymorphisms of VEGF (rs 2010963), (rs 699947), (rs 3025039). The genotyping was performed by PCR-RFLP analysis. Results: Our results revealed a marginally significant association of the –2578CC genotype (p=0.002) with a greater degree of tumor spread (Т2–Т4). Heterozygous genotypes –2578СА and +936СT carriers were included into the follow-up group significantly more often (р=0.021 and р=0.012, respectively). Our study demonstrate that VEGF –2578A/C and +936C/T polymorphisms are among the factors determining the individual peculiarities of NSCLC course in this population and can be used for clarifying the prognosis of the disease.

The effect of polymorphic variants of the DNMT3B gene on the risk of non-small cell lung cancer (NSCLC) development and its clinical characteristics was assessed. To identify rs1569686 (–579G > T) and rs2424913 (–149C > T) polymorphisms in the promoter region of the DNMT3B gene, a PCR-RFLP method was used. The risk significance of –579GT + TT (OR = 1.73; 95% CI: 1.11–2.71) and –149 CT + TT (OR = 1.59; 95% CI: 1.00–2.50) in the development of a more common tumor process in the case of non-small cell lung cancer was shown. Individuals over 60 years with the –579TT DNMT3B genotype are subjects to an increased risk of non-small cell lung cancer development (OR = 2.49; 95% CI: 1.15–5.40) and squamous cell lung cancer (OR = 4.39; 95% CI: 1.36–14.13). It was found that among smoking patients compared with non-smoking patients, there are significantly more carriers of –149TT (OR = 2.39; 95% CI: 1.16–6.93) and –579TT (OR = 3.05; 95 % CI: 1.36–6.85) genotypes. The same dependence sustained in the case of smoking patients with squamous cell lung cancer.

adenocarcinoma patients, higher expression of SHH mRNA in lung adenocarcinoma correlated with poor overall and progression free survival. A scan of 35 human lung adenocarcinoma cell lines revealed heterogeneous expression of SHH and IHH with high expression found predominantly in mutant K-Ras lines. Co-culture of high SHH expressing tumor epithelial cells and Shh-Light2 reporter cell lines demonstrated that SHH activated the fibroblast reporter in a paracrine manner, rather than an autocrine effect on cancer cells. Treatment with the SMO inhibitor, KAAD-cyclopamine, also inhibited the growth of tumor epithelial cells in co-culture with NIH-3T3 fibroblast cells but the effect was decreased when co-cultured with lung fibroblasts. Genetic loss of SHH in an autochthonous mouse model, LSL-Kras G12D/+ ;Trp53 fl/fl ; Shh fl/fl (KPS) did not affect overall survival compared to LSL-Kras G12D/+ ; Trp53 fl/fl (KP) mice However, early inhibition of the Hh pathway by anti-SHH/IHH antibody, 5E1, on KP mice resulted in significantly worse survival rates with increased metastatic burden compared to IgG treatment. Analysis of KP tumors revealed unexpected high levels of IHH mRNA by in situ hybridization and qPCR that may account for the survival differences seen between genetic ablation and pharmaceutical inhibition of the Hh ligands. Conclusion: The Hh signaling pathway acts upon lung stromal cells in a paracrine fashion and induces distinct transcriptional programs in murine embryonic and lung fibroblasts. Inhibition of paracrine Hh pathway activity in vivo worsened mortality rate due to increase in tumor growth and metastases. Furthermore, mutant Kras lung adenocarcinomas express high levels of IHH that dominates the tumor suppressive effects in our mouse models.

Conclusion:We show for the first time that SA-1 is overexpressed early in NSCLC consonant with status as a proto-oncogene. This upregulation occurs predominantly epigenetic with some contributions with genetic factors. Moreover, SA-1 may have important prognostic markers underscoring its importance of HOC regulation in NSCLC. Further studies are ongoing to elucidate the precise role of SA-1 in the pathogenesis and natural history of NSCLC.

Conclusion: EGFR mutation was associated with slow growth of the tumor, although the growth rate may be influenced by concomitant mutation of other driver genes. This may be one of the reasons that the clinical response of tyrosine kinase inhibitors are poor in some patients with EGFR mutation. Assessment of tumor aggressiveness by molecular profiling and by sequential CT are both important for the practice of precision medicine.