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.

1 Follower
56 Reads
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Journal of dermatological science 08/2015; DOI:10.1016/j.jdermsci.2015.08.003 · 3.42 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    eLife Sciences 07/2015; 4. DOI:10.7554/eLife.09519 · 9.32 Impact Factor
    • "They are novel mechanisms in tumor biology that generate de novo consensus-binding motifs for E-twenty-six transcription factors, increase the activity of the TERT promoter, and have potential clinical applications and prognostic value (Huang et al. 2013, Landa et al. 2013, Liu et al. 2013b). The purpose of this study was to analyze the prevalence, histomorphology, and follow-up data of a cohort of PTC patients enriched for patients with a known adverse clinical outcome (ACO) based on a population of 1.3 million inhabitants over a 16-year period and to determine the threshold of TC within a given PTC that could impact patient outcome. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The tall cell variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diagnostic criteria remain inconsistent and the role of a minor tall cell (TC) component is unclear. Molecular diagnostic markers are not available; however, there are two potential candidates: BRAF V600E and TERT promoter mutations. Using a novel approach, we enriched a collective with PTC harboring an adverse outcome, overcoming the limited statistical power of most studies. This enabled us to review 125 PTC patients, 57 of them with an adverse outcome. The proportion of TC that constitute a poor prognosis was assessed. All tumors underwent sequencing for TERT promoter and BRAF V600E mutational status and were stained with an antibody detecting the BRAF V600E mutation. A 10% cut off for TC was significantly associated with advanced tumor stage and lymph node metastasis. Multivariate analysis showed that tall cells above 10% were the only significant factor for overall, tumor-specific and relapse-free survival. 7% of cases had a TERT promoter mutation while 61% demonstrated a BRAF mutation. The presence of TC was significantly associated with TERT promoter and BRAF mutations. TERT predicted highly significant tumor relapse (p<0.001). PTC comprising of at least 10% TC are associated with an adverse clinical outcome and should be reported accordingly. BRAF did not influence patient outcome. Nevertheless, a positive status should encourage the search for tall cells. TERT promoter mutations are a strong predictor of tumor relapse but their role as a surrogate marker for TC is limited.
    Endocrine Related Cancer 04/2015; 22(3). DOI:10.1530/ERC-15-0057 · 4.81 Impact Factor
Show more

Similar Publications