Two glioma risk variants, TERTrs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10(-8)) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10(-5)), respectively.
The results of this meta-analysis suggest that the TERTrs2853669 polymorphism is associated with a significantly increased risk of cancer, particularly lung cancer, in Asian populations.
As a result, 15 SNPs on or near 12 genes and one miRNA with strong evidence of association with lung cancer risk were identified, including TERT (rs2736098), CHRNA3 (rs1051730), AGPHD1 (rs8034191), CLPTM1L (rs401681 and rs402710), BAT3 (rs3117582), TRNAA (rs4324798), ERCC2 (Lys751Gln), miR-146a2 (rs2910164), CYP1B1 (Arg48Gly), GSTM1 (null/present), SOD2 (C47T), IL-10 (-592C/A and -819C/T), and TP53 (intron 6).
We constructed a recombinant adenovirus containing the human sodium iodide symporter (hNIS) gene directed by the hTERT promoter, characterized the ability of infected cells in uptaking iodide, and explored the therapeutic efficacy of (131)I in a lung cancer cell line in vitro.
Our data demonstrated that hTERT promoter-driven IFN-beta expression was the tumor-specific, decreased the cell viability of tumor cells but not normal cells, and induced tumor cell apoptosis via activation of caspase pathway and release of cytochrome c. AAV-mediated IFN-beta expression driven by hTERT promoter significantly suppressed the growth of colorectal cancer and lung cancer xenograft in mice and resulted in tumor cells death in vivo.
In the logistic regression analysis, TERT-rs2853669, rs2736108, and CLPTM1L-rs31490 were significant associated with increased risk of lung cancer (OR = 1.46, 95% CI = 1.22-1.75; OR = 1.22, 95% CI = 1.00-1.49 and OR = 1.74, 95% CI = 1.35-2.23 under additive model, respectively).
In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.
We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8p21.1 with p value = 7.4 × 10(-6)), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk.
Single-nucleotide polymorphisms rs421629 on 5p15.33 and rs1948, rs660652, rs8040868 and rs2036527 on 15q25.1, previously identified as lung cancer risk or nicotine-addiction modifiers, were associated with tumor DNA methylation levels in the promoters of TERT and CHRNB4 (P<0.001), respectively, in two independent sample sets (n=82; n=150).
We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies.
Accumulating evidence has suggested that TERT could modulate the expression of numerous genes including interleukin 6 (IL-6), an important cytokine for the development of lung cancer.
We detected the epidermal growth factor receptor L858R, MSH2 R929* and telomerase reverse transcriptase amplification in the lung cancer specimen; CDH1 c.1320+1G>T mutation in the gastric cancer (GC) specimen; and MLH1 c.1896+5G>A germline mutation in the lung and GC specimens by 450 cancer-related gene mutations detection using next-generation sequencing technology.
We evaluated the antitumor activity of the Bax gene and green fluorescent protein/tumor necrosis factor-related apoptosis-inducing ligand (GFP/TRAIL) fusion gene driven by the human telomerase reverse transcriptase promoter both separately and combined in the human ovarian cancer lines SKOV3ip and DOV13 and human lung cancer line H1299.
These results suggest that genetic variants in the TERT-CLPTM1L gene may predispose individuals to be susceptible to LC, particularly NSCLC, in the Chinese population.
By chromosome conformation capture, it was identified that the segment containing these two SNPs could interact with TERT (telomerase reverse transcriptase) promoter, thus indicating that these SNPs confer lung cancer risk by regulating TERT expression instead of CLPTM1L.
Our results suggest that a common functional promoter polymorphism, TERTrs2853669, may influence both telomere length and lung cancer risk in the Korean population.
The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P = 6.3 × 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 × 10(-6)).