hTERT gene dosage correlates with telomerase activity in human lung cancer cell lines

Saretzki, Gabriele; Petersen, Simone; Petersen, Iver; Kölble, Konrad; Zglinicki, Thomas von

doi:10.1016/s0304-3835(01)00644-9

Cited by 38 publications

(26 citation statements)

References 23 publications

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“…[21][22][23][24][25][26] In this study, all HCCs demonstrated higher hTERT mRNA levels than their corresponding non-tumorous tissues, and the positive correlation between hTERT level and TA in our study supports previous studies which showed that hTERT is a key regulator of TA in hepatocarcinogenesis. [27][28][29][30] In addition, hTERT mRNA levels were positively correlated with TLs and HCCs with high TA showed minimal shortening or even lengthening of telomeres, suggesting that telomerase may play a significant role in telomere maintenance or lengthening during HCC progression. Furthermore, advanced tumor stage and poorer overall survival were seen in HCCs with strong TA supporting previous reports that Figure 5 Kaplan-Meier curve for overall survival of HCC patients according to telomerase activity (TA) (a), telomere length ratio (TL ratio) of the HCC to the non-tumorous livers (b), and multipolar mitosis (MM) count (c).…”

Section: Discussionmentioning

confidence: 97%

High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis

Kim

Park

et al. 2008

Laboratory Investigation

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Telomerase reactivation and telomere maintenance are crucial in carcinogenesis and tumor progression. In this study, the relationships between telomere parameters, chromosomal instability and clinicopathological features were evaluated in hepatocellular carcinomas (HCCs). Telomere length (TL), telomerase activity (TA) and human telomerase reverse transcriptase (hTERT) mRNA levels were measured in 49 hepatitis B virus (HBV)-related HCCs and corresponding non-tumorous tissues. The results were compared with clinicopathological data, including differentiation, multipolar mitosis (MM), anaphase bridge, immunohistochemical stain results for cytokeratin 19 (CK19) and patient outcome. TL of HCCs ranged from 4.7 to 13.1 kb, and 44.4% of HCCs showed telomere lengthening. hTERT mRNA levels and TA were closely related (P ¼ 0.008), and were significantly higher in HCCs than non-tumorous tissues. TL was significantly higher in HCCs with strong TA (P ¼ 0.048), high hTERT mRNA levels (P ¼ 0.001) and poor differentiation (P ¼ 0.041). Frequent MM was associated with poor differentiation (P ¼ 0.007) and advanced stage (Po0.001). TA was positively correlated with MM, anaphase bridges and advanced stage (P ¼ 0.019, P ¼ 0.017 and P ¼ 0.029). Thirteen (28.3%) HCCs were CK19 þ and demonstrated longer telomeres than CK19À HCCs (P ¼ 0.046). Overall survival was poor in HCCs with MM 40.4 per field (P ¼ 0.016), high TA (P ¼ 0.009) and high TL ratio (HCC/non-HCC) 40.8 (P ¼ 0.044). Our results show that long telomeres, high TA and high mitotic instability are poor prognostic markers for HBV-related HCCs and their close association suggests that telomere maintenance may be important for the progression of HCCs with high chromosomal instability to more aggressive ones.

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Section: Discussionmentioning

confidence: 97%

High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis

Kim

Park

et al. 2008

Laboratory Investigation

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“…Strikingly, of the six recurrent amplified regions defined, five (Regions A2-A6) have not been previously reported in SqCC. The previously reported amplification at 5p15 (Bryce et al, 2000;Saretzki et al, 2002), which contains the well-characterized Human Telomerase Reverse Transcriptase gene (hTERT), falls within Region A1. However, the other locus known to be amplified in tumors (5p13.2), containing S-phase kinase-associated protein 2 (Skp2), although detected in the array CGH tumor profiles, did not qualify as a region of interest in our study due to the absence of amplification in the CIS samples at this locus (Zhu et al, 2004).…”

Section: Novel Amplifications Defined In Cis Lesionsmentioning

confidence: 99%

Chromosome 5p aberrations are early events in lung cancer: implication of glial cell line-derived neurotrophic factor in disease progression

Garnis¹,

Davies²,

Buys³

et al. 2005

Oncogene

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Lung cancer is the most widely diagnosed malignancy in the world. Understanding early-stage disease will give insight into its pathogenesis. Despite the fact that preinvasive lesions are challenging to isolate, and often yield insufficient DNA for the analysis of multiple loci, genomic profiling of such lesions will lead to the discovery of causal genetic alterations, which may be otherwise masked by the gross instability associated with tumors. In this study, we report the identification of multiple early genetic events on chromosome 5p in lung cancer progression. Using a highresolution 5p-specific genomic array, which contains a tiling path of DNA segments for comparative genomic hybridization, nine novel minimal regions of loss and gain were discovered in bronchial carcinoma in situ (CIS) specimens. Within these regions we identified two candidate genes novel to lung cancer. The 0.27 Mbp region at 5p15.2 contains a single gene, Triple Functional Domain, which we determined to be differentially expressed in tumors. The 0.34 Mbp region at 5p13.2 contains Glial Cell Line-Derived Neurotrophic Factor (GDNF), which is a ligand for the RET oncogene product and is normally expressed during lung development (but absent in adult lung tissue). Our data showed not only that GDNF is overexpressed at the transcript level in squamous non-small-cell lung carcinoma, but also that the GDNF protein is present in early-stage lesions. Reactivation of the fetal lung expressed GDNF in early lesions and its amplification in CIS suggests an early role in tumorigenesis. These results highlight the value of examining the genomes of pre-invasive stages of cancer at tiling resolution.

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“…There is considerable evidence that transcriptional activation plays a major role in regulating hTERT mRNA expression (Ducrest et al, 2002), and the latter is correlated with telomerase activity (Arinaga et al, 2000;Marchetti et al, 2002;Saretzki et al, 2002). However, post-translational modifications may also contribute to the regulation of hTERT activity (Kang et al, 1999).…”

mentioning

confidence: 99%

“…The hTERT gene is located on chromosome 5p15, a chromosomal arm that is commonly overepresented or amplified in lung cancer (Luk et al, 2001). Amplification of the hTERT gene and a concomitant increase in telomerase activity has been reported in lung cancer cell lines and other cancer types (Zhang et al, 2000;Saretzki et al, 2002). In this study, we have investigated the frequency and prognostic significance of hTERT gene amplification and overexpression in NSCLC.…”

mentioning

confidence: 99%

Amplification of telomerase (hTERT) gene is a poor prognostic marker in non-small-cell lung cancer

et al. 2006

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Telomerase reactivation is a hallmark of human carcinogenesis. Increased telomerase activity may result from gene amplification and/or overexpression. This study evaluates the prognostic value of hTERT gene amplification and mRNA overexpression in 144 resectable non-small-cell lung cancer (NSCLC) specimens. The hTERT gene copy number was assessed by quantitative polymerase chain reaction (qPCR) on laser-capture microdissected tumour cells of 81 tumours, and by fluorescence in situ hybridisation (FISH) on a subset of 59 tumours. hTERT mRNA level was determined by reverse transcription (RT) -qPCR in 130 tumours. In total, 57% of (46 out of 81) primary NSCLC specimens demonstrated hTERT amplification, which was significantly more common (Po0.001) in adenocarcinoma (30 out of 40) than in squamous cell carcinoma (13 out of 37). The hTERT mRNA overexpression was noted in 74% (94 out of 130) of tumours; it was more frequent in squamous cell than in adenocarcinoma (87 vs 68%, P ¼ 0.03). Overexpression was significantly associated with amplification (P ¼ 0.03), especially in adenocarcinoma. The hTERT gene amplification was prognostic for shorter recurrence-free survival (hazard ratio ¼ 2.16, P ¼ 0.03). These data indicate that gene amplification is an important mechanism for hTERT overexpression in lung adenocarcinoma and is an independent poor prognostic marker for disease-free survival in NSCLC.

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hTERT gene dosage correlates with telomerase activity in human lung cancer cell lines

Cited by 38 publications

References 23 publications

High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis

High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis

Chromosome 5p aberrations are early events in lung cancer: implication of glial cell line-derived neurotrophic factor in disease progression

Amplification of telomerase (hTERT) gene is a poor prognostic marker in non-small-cell lung cancer

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