Cancer Letters

Cancer Letters

Volume 240, Issue 1, 18 August 2006, Pages 148-156
Cancer Letters

Elevation of telomerase activity positively correlates to poor prognosis of patients with non-small cell lung cancer

https://doi.org/10.1016/j.canlet.2005.09.005Get rights and content

Abstract

Increased telomerase activity has been found in various types of human malignancies, including lung cancer. However, the correlation between the level of telomerase activity and the clinical characteristics of lung cancer patients remains unclear. The levels of telomerase activity in lung cancer specimens and adjacent non-neoplastic tissues obtained from 68 patients who underwent surgery were measured by using a non-radioactive quantitative method. Clinical and pathologic parameters were evaluated with respect to the level of telomerase activity. Prominent telomerase activity was detected in 58 (85.3%) lung cancer tissues and 21 (30.9%) adjacent non-neoplastic tissues. There was a trend of increase in relative telomerase activity in regard to the advanced pathological stage, and lymph node metastasis. Using Cox regression analysis, we found that every 100 unit of increase in relative telomerase activity was associated with an increase in the hazard ratio of death by 13% after controlling for other variables such as age, gender, and stage (Hazard ratio=1.13; 95% CI: 1.03–1.23, P=0.006). For patients with stage I disease, an increase of every 100 unit of relative telomerase activity was associated with an even higher increase of 33% in the hazard ratio of death (Hazard ratio=1.33; 95% CI: 1.07–1.65, P=0.011) and a 16% increase in the hazard of disease recurrence (Hazard ratio=1.16, 95% CI: 1.01–1.33, P=0.032). The level of telomerase activity is positively correlated with the risk of recurrence and mortality of lung cancer. The level of telomerase activity would predict the prognosis of lung cancer patients.

Introduction

Lung cancer is the leading cause of cancer mortality in most countries, including Taiwan [1], [2]. Approximately 80% of cases are classified histologically as non-small cell lung cancer, with a 5-year survival rate of only 14% [3], [4]. Surgical removal is the main option for the successful treatment of primary lung cancer, but widespread dissemination often defeats this mode of treatment. Most of the lung cancer patients still die of distant metastases even after surgery. Pre-operative variables that affect the survival of patients with non-small cell lung cancer have been identified [5], [6], [7]. For example, tumor size, vascular invasion, poor differentiation, high tumor-proliferative index and several genetic alterations, including K-ras [8], [9] and p53 [7], [10] mutations, have all been implicated with prognostic significance. In addition, multiple independently assessed genes or gene products have been demonstrated to have prognostic significance for lung cancer [11], [12], [13].

Human telomerase is a ribonucleoprotein that adds repeated units of TTAGGG to the ends of telomeres [14]. Telomerase activity has been found in 87% of all human tumors [15], [16], [17]. In contrast, in normal somatic cells, telomerase activity is usually undetectable [15]. Gradients of increasing ratios for positive telomerase activity have been observed in the respiratory epithelium during the multi-stage pathogenesis of lung carcinoma [18], [19]. Telomerase activity is one of the most important prognostic factors in patients with non-small cell lung cancer [20]. Similar correlations have been reported for other types of malignancies [21], [22], [23].

Telomerase activity has been detected in almost all small cell lung cancer and in 80% of non-small cell lung cancer [24]. The detection of telomerase might be of little use in predicting the prognosis of lung cancer patients since most of the patients have positive telomerase activity. Little has been studied on the quantitative analysis of telomerase activity and the subsequent outcomes. We hypothesize that the quantification of telomerase activity, rather than detection, would predict the prognosis of lung cancer patients. In this study, we used a non-radioactive quantitative method to investigate the correlation between the level of telomerase activity and the clinical features in patients with non-small cell lung cancer.

Section snippets

Patients and specimens

Patients who underwent surgery for non-small-cell lung cancer at National Taiwan University Hospital were included as potential subjects in this study. The Institutional Review Board of National Taiwan University Hospital approved this study. None of the patients had received neoadjuvant chemotherapy or radiation therapy before surgery. Specimens of lung cancer tissue and adjacent normal lung tissue obtained at surgery were immediately snap-frozen in liquid nitrogen and stored at −80 °C until

Results

Lung cancer and adjacent non-neoplastic tissues were obtained from 68 patients (48 men and 20 women), ranging in age from 41 to 80 years (mean 64.8 years) who underwent surgery from January to December 2000. The most common histological type was adenocarcinoma (52.9%), followed by squamous cell carcinoma (41.1%) and large carcinoma (6.0%). The proportion of patients in pathological stages, tumor invasion, and lymph node metastasis are shown in Table 1. These patients were followed up clinically

Discussion

In this study, the telomerase activity was analyzed by a non-radioactive quantitative method, revealing that the increase of telomerase activity correlated with an advance in lung cancer stage, tumor invasion, and lymph node metastasis. Our study demonstrates that an increase in telomerase activity level correlates significantly with an increased hazard ratio of death. For patients with stage I disease, the increase in telomerase activity level had a statistically positive correlation with the

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