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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    • "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.
    Journal of dermatological science 08/2015; DOI:10.1016/j.jdermsci.2015.08.003 · 3.42 Impact Factor
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    • "Translational efficiency may also be influenced by modifications in the noncoding portion of the genes. Changes in the promoter region and alternative promoter usage during the process of transcription and post-transcriptional regulation may lead to transcripts exhibiting reduced or enhanced translational efficiency in plants and animals (Larsen et al. 2002; Hong et al. 2012; Huang et al. 2013). Although studying promoter regions was out of the scope of this work, our analysis of nine Picea families of different sizes showed a greater variation of motifs (located 1 kb upstream UTR sequences) in large gene families (showing a lower codon bias) than in single-copy and small gene families (showing a higher codon bias). "
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    ABSTRACT: The recent sequencing of several gymnosperm genomes has greatly facilitated studying the evolution of their genes and gene families. In this study, we examine the evidence for expression-mediated selection in the first two fully sequenced representatives of the gymnosperm plant clade (Picea abies and Picea glauca). We use genome-wide estimates of gene expression (>50,000 expressed genes) to study the relationship between gene expression, codon bias, rates of sequence divergence, protein length and gene duplication. We found that gene expression is correlated with rates of sequence divergence and codon bias, suggesting that natural selection is acting on Picea protein-coding genes for translational efficiency. Gene expression, rates of sequence divergence and codon bias are correlated with the size of gene families, with large multi-copy gene families having, on average, a lower expression level and breadth, lower codon bias, and higher rates of sequence divergence than single-copy gene families. Tissue-specific patterns of gene expression were more common in large gene families with large gene expression divergence than in single copy families. Recent family expansions combined with large gene expression variation in paralogs and increased rates of sequence evolution suggest that some Picea gene families are rapidly evolving to cope with biotic and abiotic stress. Our study highlights the importance of gene expression and natural selection in shaping the evolution of protein-coding genes in Picea species, and sets the ground for further studies investigating the evolution of individual gene families in gymnosperms. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
    Genome Biology and Evolution 03/2015; 7(4). DOI:10.1093/gbe/evv044 · 4.23 Impact Factor
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    • "Taken together , our data show that the prognostic impact of TERTp - mut is highly contextual and depends on the histologic and genomic background of the tumour . From a mechanistic point of view , TERTp mutation leads to the creation of a putative binding site for Ets / TCF transcription factors ( Huang et al , 2013 ) , leading to a two - to four - fold higher expression of telomerase ( Arita et al , 2013 ; Huang et al , 2013 ; Nault et al , 2013 ; Rachakonda et al , 2013 ) . The activity of telomerase reverse transcriptase is closely correlated with TERT mRNA level . "
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    ABSTRACT: Background: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter. Methods: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. Results: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation. Conclusions: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors.
    British Journal of Cancer 10/2014; 111(10). DOI:10.1038/bjc.2014.538 · 4.84 Impact Factor
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