Telomeres play a key role in the maintenance of chromosome integrity and stability. There is growing evidence that short telomeres induce chromosome instability and thereby promote the development of cancer. We investigated the association of telomere length and the risk of lung cancer. Relative telomere length in peripheral blood lymphocytes was measured by quantitative polymerase chain reaction in 243 lung cancer patients and 243 healthy controls that were frequency-matched for age, sex and smoking status. Telomere length was significantly shorter in lung cancer patients than in controls (mean ± standard deviation: 1.59 ± 0.75 versus 2.16 ± 1.10, P < 0.0001). When the subjects were categorized into quartiles based on telomere length, the risk of lung cancer was found to increase as telomere length shortened (P trend < 0.0001). In addition, when the median of telomere length was used as the cutoff between long and short telomeres, individuals with short telomeres were at a significantly higher risk of lung cancer than those with long telomeres (adjusted odds ratio = 3.15, 95% confidence interval + 2.12-4.67, P < 0.0001). When the cases were categorized by tumor histology, the effect of short telomere length on the risk of lung cancer was more pronounced in patients with small cell carcinoma than in those with squamous cell carcinoma and adenocarcinoma (P + 0.001, test for homogeneity). These findings suggest that shortening of the telomeres may be a risk factor for lung cancer, and therefore, the presence of shortened telomeres may be used as a marker for susceptibility to lung cancer. T elomeres are nucleoprotein complexes composed of noncoding TTAGGG repeats and associated telomere binding proteins. The main function of telomeres is to cap the ends of chromosomes and to protect chromosomes from degradation, end-to-end fusion and atypical recombination.(1) Telomeres are approximately 10-15 kb in human somatic cells, and they shorten by 50-200 bp with each cell division, (2) primarily as a result of incomplete replication of linear chromosomes by conventional DNA polymerases (known as the end replication problem). (3)(4)(5) This progressive shortening of the telomere limits the replicative capacity of human somatic cells to 50-80 cell divisions and serves as a 'mitotic clock' that defines the lifespan of somatic cells. (6,7) When the telomeres reach a critical length, cells undergo either irreversible growth arrest, called cellular senescence, or apoptosis. (8,9) In addition to the role of telomere shortening in organismal aging, it has been proposed that short telomeres suppress tumor formation by limiting the proliferation of transformed cells. (8,10,11) However, in contrast to this hypothesis, it has also been reported that cancer risk sharply increases in response to telomere shortening during aging and chronic illness. (12) Moreover, several studies have demonstrated that cancer cells have shorter telomeres than the surrounding non-malignant cells. (13,14) Additionally, studies of telomerase knockout mice ...

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Although immune checkpoint inhibitors have resulted in durable clinical benefits in a subset of patients with advanced cancer, some patients who did not respond to initial anti-PD-1 therapy have been found to benefit from the addition of salvage chemotherapy. However, the mechanism responsible for the successful chemoimmunotherapy is not completely understood. Here we show that a subset of circulating CD8+ T cells expressing the chemokine receptor CX3CR1 are able to withstand the toxicity of chemotherapy and are increased in patients with metastatic melanoma who responded to chemoimmunotherapy (paclitaxel and carboplatin plus PD-1 blockade). These CX3CR1+CD8+ T cells have effector memory phenotypes and the ability to efflux chemotherapy drugs via the ABCB1 transporter. In line with clinical observation, our preclinical models identified an optimal sequencing of chemoimmunotherapy that resulted in an increase of CX3CR1+CD8+ T cells. Taken together, we found a subset of PD-1 therapy-responsive CD8+ T cells that were capable of withstanding chemotherapy and executing tumor rejection with their unique abilities of drug efflux (ABCB1), cytolytic activity (granzyme B and perforin), and migration to and retention (CX3CR1 and CD11a) at tumor sites. Future strategies to monitor and increase the frequency of CX3CR1+CD8+ T cells may help to design effective chemoimmunotherapy to overcome cancer resistance to immune checkpoint blockade therapy.

DNA-methyltransferase-3B (DNMT3B) plays an important role in the generation of aberrant methylation in carcinogenesis. Polymorphisms and haplotypes of the DNMT3B gene may influence DNMT3B activity on DNA methylation, thereby modulating the susceptibility to lung cancer. To test this hypothesis, we investigated the association of the -283T > C (from exon 1A transcription start site) and -579G > T (from exon 1B transcription start site) polymorphisms in DNMT3B promoter, and their haplotypes with the risk of lung cancer in a Korean population. The DNMT3B genotype was determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and sex. Individuals with at least one -283T allele were at a significantly decreased risk of adenocarcinoma (AC) and small cell carcinoma (SM) [adjusted odds ratio (OR) = 0.48, 95% confidence interval (CI) = 0.28-0.82, P = 0.007; and adjusted OR = 0.47, 95% CI = 0.24-0.93, P = 0.03, respectively] compared with those harboring a -283CC genotype. Individuals with at least one -579G allele were also at a significantly decreased risk of AC and SM (adjusted OR = 0.47, 95% CI = 0.28-0.81, P = 0.006; and adjusted OR = 0.51, 95% CI = 0.26-0.99, P = 0.048, respectively) compared with those having a -579TT genotype. The -283T allele was linked with the -579G allele, and haplotype -283T/-579G was associated with a significantly decreased risk of AC (adjusted OR = 0.48, 95% CI = 0.29-0.81, P = 0.006) as compared with haplotype -283C/-579T. In a promoter assay, carriage of the -283T allele showed a significantly lower promoter activity ( approximately 50%) compared with the -283C allele (P < 0.001), but the -579G > T polymorphism did not have an affect on the DNMT3B promoter activity. These results suggest that the DNMT3B -283T > C polymorphism influences DNMT3B expression, thus contributing to the genetic susceptibility to lung cancer.

Angiogenesis is an essential process in the development, growth, and metastasis of malignant tumors including lung cancer. DNA sequence variations in the vascular endothelial growth factor (VEGF) gene may lead to altered VEGF production and/or activity, thereby causing interindividual differences in the susceptibility to lung cancer via their actions on the pathways of tumor angiogenesis. To test this hypothesis, we investigated the potential association between three VEGF polymorphisms (À À460T > C, +405C > G, and 936C > T)/haplotypes and the risk of lung cancer in a Korean population. VEGF genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency matched for age and sex. VEGF haplotypes were predicted using Bayesian algorithm in the phase program. Compared with the combined +405 CC and CG genotype, the +405 GG genotype found associated with a significantly decreased risk of small cell carcinoma [SCC; adjusted odds ratio (OR), 0.36; 95% confidence interval (95% CI), 0.17-0.78]. The 936 CT genotype and the combined 936 CT and TT genotype were also associated with a significantly decreased risk of SCC compared with the 936 CC genotype (adjusted OR, 0.47; 95% CI, 0.26-0.85 and adjusted OR, 0.44; 95% CI, 0.24-0.80, respectively). Haplotype CGT was associated with a significantly decreased risk of SCC (adjusted OR, 0.39; 95% CI, 0.18-0.87), whereas haplotype TCC conferred a significantly increased risk of SCC (adjusted OR, 1.63; 95% CI, 1.14-2.33). None of the VEGF polymorphisms studied significantly influenced the susceptibility to lung cancer except SCC. However, haplotypes TCT and TGT were significantly associated with the risk of overall lung cancer, respectively (adjusted OR, 0.38; 95% CI, 0.25-0.60 and adjusted OR, 3.94; 95% CI, 2.00-7.76, respectively). These effects of haplotypes TCT and TGT on lung cancer risk were observed in three major histologic types of lung cancer. These results suggest that the VEGF gene may be contribute to an inherited predisposition to lung cancer.