Telomere Length and Recurrence Risk after Curative Resection in Patients with Early-Stage Non–Small-Cell Lung Cancer: A Prospective Cohort Study

Abstract

Background We hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence after curative resection in non-small cell lung cancer (NSCLC). Methods This prospective study included 473 patients with histologically confirmed early stage NSCLC who underwent curative resection at MD Anderson Cancer Center between 1995 and 2008. Relative telomere length (RTL) of peripheral leukocytes was measured by real-time PCR. The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model. Results Median duration of follow-up was 61 months and 151 patients (32%) had developed recurrence at time of analysis. Patients who developed recurrence had significantly longer mean RTL compared to those without recurrence (1.13 vs 1.07, P=0.046). A subgroup analysis indicates that women had longer RTL compared to males (1.12 vs 1.06, P=0.025), and the patients with adenocarcinoma demonstrated longer RTL compared to those with other histologic types (1.11 vs 1.05, P=0.042). To determine if longer RTL in women and adenocarcinoma subgroup would predict risk of recurrence, multivariate Cox analysis adjusting for age, gender, stage, pack year and treatment regimens was performed. Longer telomeres were significantly associated with higher risk of developing recurrence in female (HR=2.25; 95% CI, 1.02-4.96, P=0.044) and adenocarcinoma subgroups (HR=2.19; 95% CI, 1.05-4.55, P=0.036). The increased risk of recurrence due to long RTL was more apparent in females with adenocarcinoma (HR=2.67; 95% CI, 1.19-6.03, P=0.018). Conclusions This is the first prospective study to suggest that long RTL is associated with recurrence in early stage NSCLC after curative resection. Women and adenocarcinoma appear to be special subgroups in which telomere biology may play an important role.

Systematic Review of Genetic Variation in Chromosome 5p15.33 and Telomere Length as Predictive and Prognostic Biomarkers for Lung Cancer

“…Weischer and colleagues evaluated lung cancer patients identified from a 20year prospective follow-up of a population-based sample of 47,102 individuals in Denmark (48). Kim and colleagues collected information from 467 lung cancer patients enrolled at MD Anderson Cancer Center in Houston, Texas (60). PBLs are the most common tissue of choice for measuring TL in studies that involve cancer-free individuals and are considered to be an acceptable surrogate for TL in other tissues or organs of interest.…”

“…In contrast, tumor TL can be more heterogeneous and reflect the cumulative impact of many tumor-associated factors that influence telomere homeostasis. Both studies using PBL collected samples prior to treatment, and Weischer and colleagues obtained blood prior to cancer diagnosis (48,60). Therefore, the findings of these studies are unlikely to be confounded by treatment.…”

“…Disease recurrence and progression. Definitions of PFS were very similar among the three observational studies of TL, although only Kim and colleagues (60) specified which sites were included in the recurrence definition. All three studies reported statistically significant associations between TL and cancer recurrence; however, the HRs were in opposing directions ( The imetelstat trial did not observe any statistically significant differences in PFS between short and long TL strata (59).…”

“…Therefore, longer TL may be a marker for the acquired enhanced proliferative and survival capacity of malignant cells, which would in turn translate to more aggressive disease. Longer TL may allow for more actively reproducing cells, leading to an accumulation of mutations affecting apoptosis and senescence pathways, and increase the number of viable tumor cells (60,74). In addition, the sustained replication of unstable tumor cells with longer TL may allow for somatic evolution, such as the acquisition of mutations that contribute to the emergence of clones with enhanced capacity for invasion and metastasis (43,75,76).…”

Association of telomere length in peripheral leukocytes with chronic hepatitis B and hepatocellular carcinoma

“…Some findings showed that shorter telomere length not only increases the risk of gastric cancer, [12] but also decreases the survival rate of bladder cancer, [13] while in other epidemiologic investigates, longer telomere length was associated with the increased risk of cancers that were reported. [14–18] To date, little research has investigated the relationship between telomere length and the event of hepatocarcinogenesis (from normal, CHB to HCC) to our knowledge. In this study, the changes of leukocytes telomere length in different cohorts of diseases in a southwest Han Chinese population were investigated to try to understand the relationship of RTL in different stages of hepatocarcinogenesis.…”