Telomere length and the risk of lung cancer

Abstract

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 ...

Telomere length and LINE1 methylation is associated with chromosomal aberrations in peripheral blood

“…The associations generally remained after adjustment for age and are probably fairly robust as the chromosomal aberrations scoring has been validated (Savage, 1976;Brøgger et al, 1990) and the telomere length and the LINE1 methylation analyses demonstrated low coefficients of variation (Jang et al, 2008; Mumford et al, 2008;Shen et al, 2009;Hossain et al, 2012). The finding of more LINE1 methylation with higher frequency of chromosomal aberrations was in contrast to expected.…”

“…Telomeres are of great importance in maintaining chromosomal stability and cellular DNA damage and repair (Hahn, 2003;Callen and Surralles, 2004;Blasco, 2005;Rodier et al, 2005). Short average telomere length in peripheral blood appears to be a susceptibility marker for human breast, bladder, head and neck, lung, and renal cell cancers (Wu et al, 2003;Broberg et al, 2005;Shen et al, 2007;Jang et al, 2008) and meta studies show that the presence of shortened telomeres is a marker for susceptibility to human cancer, but for which cancer types is not clearly established Wentzensen et al, 2011). Short telomere length caused chromosomal instability and epithelial carcinogenesis in mice (Artandi et al, 2000).…”

Pharmacogenomic Approach of Telomerase in Cancer: Importance of End Zone Variability

“…The authors found evidence of heterogeneous effects according to cancer type, whereby tumors with a high fatality rate tended to exhibit more prominent relationships with telomere length and tumors with a more favorable prognosis showed modest or no associations. These results corroborate with previous evaluations demonstrating a link between short telomere length and lung cancer, bladder cancer, renal cell carcinoma, non-Hodgkin lymphoma and head and neck tumors (Wu, Amos et al 2003;Broberg, Bjork et al 2005;McGrath, Wong et al 2007;Shao, Wood et al 2007;Jang, Choi et al 2008;Lan, Cawthon et al 2009), but failed to obtain significant correlations between short telomere length and colorectal and breast cancer (De Vivo, Prescott et al 2009;Shen, Gammon et al 2009;Zee, Castonguay et al 2009). A variety of experimental and genetic studies support the hypothesis that telomere attrition contributes to the manifestation and dissemination of malignancies.…”

“…However, previous reports from this research area are not unambiguous. In renal, lung, bladder, head and neck and oesophagus carcinomas, short TL in peripheral blood have been associated with increased cancer risk (Wu, Amos et al 2003;McGrath, Wong et al 2007;Risques, Vaughan et al 2007;Jang, Choi et al 2008). Similar data have been reported for malignant lymphoma (Widmann, Herrmann et al 2007).…”

Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study

“…In recent years, several epidemiological studies (case-control and/or cohort) have reported on the association between TL and a number of cancers such as lung, 7,8 breast, [9][10][11] bladder, 12,13 renal, 14,15 gastric, 16,17 esophageal, 18,19 colorectal, 20,21 and lymphomas. 22,23 Interestingly, according to the most recent meta-analysis on TL and cancer, reported results of What's new?…”