Highly Recurrent TERT Promoter Mutations in Human Melanoma

The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Science (Impact Factor: 33.61). 01/2013; 339(6122). DOI: 10.1126/science.1229259
Source: PubMed


Systematic sequencing of human cancer genomes has identified many recurrent mutations in the protein-coding regions of genes
but rarely in gene regulatory regions. Here, we describe two independent mutations within the core promoter of telomerase reverse transcriptase (TERT), the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) melanomas examined.
These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, and in reporter assays,
the mutations increased transcriptional activity from the TERT promoter by two- to fourfold. Examination of 150 cancer cell lines derived from diverse tumor types revealed the same mutations
in 24 cases (16%), with preliminary evidence of elevated frequency in bladder and hepatocellular cancer cells. Thus, somatic
mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.

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    • "The mechanism of pTERTm in cancer progression is still unclear. It has been reported that pTERTm is able to increase the transcriptional activity of TERT promoter in tumours and express higher level of TERT mRNA compared with wild type-tumours[7,8,11,33,39,56]. In this regard, it is conceivable that the acquisition of pTERTm leading to TERT activation is an important event during cancer progression, as it allows tumour cells to avoid proliferation limitation and to acquire immortalization[37]. "
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    ABSTRACT: Background: The prevalence of telomerase reverse transcriptase (TERT) promoter mutations (pTERTm) in non-small-cell lung cancer (NSCLC) have been investigated, but the results were inconsistent. In addition, several studies have analysed the role of pTERTm in the etiology of various types of cancers, however, the results also remain inconsistent. Methods: The genomic DNA sequence of 103 NSCLC samples were analysed to investigate the frequency of pTERTm in these patients and to establish whether these mutations are associated with their clinical data. Furthermore, a meta-analysis based on previously published articles and our cohort study was performed to investigate the association of pTERTm with patient gender, age at diagnosis, metastasis status, tumour stage and cancer prognosis (5-year overall survival rate). Results: In the cohort study, 4 patients had C228T and 2 had C250T, with a total mutation frequency up to 5.8%. Significant difference of clinical data between pTERTm carriers and noncarriers was only found in age at diagnosis. In the meta-analysis, We found that pTERTm carriers in cancer patients are older than noncarriers (Mean difference (MD) = 5.24; 95% confidence interval [CI], 2.00 to 8.48), male patients were more likely to harbour pTERTm (odds Ratios (OR) = 1.38; 95% CI, 1.22 to 1.58), and that pTERTm had a significant association with distant metastasis (OR = 3.78; 95% CI, 2.45 to 5.82), a higher tumour grade in patients with glioma (WHO grade III, IV vs. I, II: OR, 2.41; 95% CI, 1.88 to 3.08) and a higher tumour stage in other types of cancer (III, IV vs. I, II: OR, 2.48; 95% CI, 1.48 to 4.15). pTERTm was also significantly associated with a greater risk of death (hazard ratio = 1.71; 95% CI, 1.41 to 2.08). Conclusions: pTERTm are a moderately prevalent genetic event in NSCLC. The current meta-analysis indicates that pTERTm is associated with patient age, gender and distant metastasis. It may serves as an adverse prognostic factor in individuals with cancers.
    Full-text · Article · Jan 2016 · PLoS ONE
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    • "There is much evidence supporting the role of telomere length in the pathogenesis of skin cancer. The incidence of skin cancer is increased following mutations in genes implicated in the maintenance of telomeres integrity [17] [18] [19] and among patients suffering from telomere-related genetic syndromes [20]. Moreover, telomere length is positively associated with nevus count [21], which is a major indicator of skin cancer risk [22] [23]. "
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    ABSTRACT: There is much evidence supporting the role of telomeres in cancer pathogenesis, however the studies that investigated the association between telomere length and skin cancer risk provided inconsistent results. To help clarify this issue, we performed a systematic review and meta-analysis of published papers on the association between peripheral leukocytes telomere length (PLTL) and the risk of cutaneous melanoma and non-melanoma skin cancer (NMSC). We calculated summary relative risks (SRR) and 95% confidence intervals (95%CI) using random effect models with maximum likelihood estimates, and explored causes of between-studies heterogeneity of risk estimates. We included 1629 cutaneous melanoma and 1439 NMSC from eight independent studies published until March 2015. The SRR of cutaneous melanoma for those in the lowest (vs. highest) category of PLTL distribution was 0.25 (95% CI 0.09-0.67). The results were less clear for NMSC, with two studies reporting no association and one study showing an increase in risk for those in the lowest (vs. highest) category of PLTL distribution. For both cutaneous melanoma and NMSC, the between-studies heterogeneity was large, mainly due to inclusion of hospital-based case-control studies. Our meta-analysis shows evidence of an association between short PLTL and reduced risk for cutaneous melanoma. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Aug 2015 · Journal of dermatological science
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    • "Now, in eLife, Dirk Hockemeyer and colleagues at the University of California, Berkeley—including Kunitoshi Chiba as first author—report progress in this direction (Chiba et al., 2015). Previous studies that evaluated the effects of TERT promoter mutations on TERT expression levels and telomerase activity in cancer cell lines had found relatively modest differences between mutant and wild type cells (Horn et al., 2013; Huang et al., 2013; Borah et al., 2015). However, by definition, all cancers must have already found a way to maintain their telomeres. "
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    ABSTRACT: Studies using human embryonic stem cells have revealed how common cancer-associated mutations exert their effect on telomerase after cells differentiate into more specialized cell types.
    Full-text · Article · Jul 2015 · eLife Sciences
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