Highly Recurrent TERT Promoter Mutations in Human Melanoma
ABSTRACT 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 TERT, the gene coding for the catalytic subunit of telomerase, which collectively occur in 50 of 70 (71%) of melanomas examined. These mutations generate de novo consensus binding motifs for ETS transcription factors, and in reporter assays the mutations increased transcriptional activity from the TERT promoter by 2- to 4-fold. 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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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 · 4.53 Impact Factor
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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 advance online publication, 14 October 2014; doi:10.1038/bjc.2014.538 www.bjcancer.com.British Journal of Cancer 10/2014; 111(10). DOI:10.1038/bjc.2014.538 · 4.82 Impact Factor
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ABSTRACT: Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors [38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck paragangliomas (HN PGLs) and 33 peripheral neuroblastic tumors] was selected along with 16 human neuroblastoma (NBL) and 2 ACC cell lines, to assess TERT promoter mutations by Sanger sequencing. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH-deficiency. TERT promoter mutations were found in 7 out of 289 tumors and in 3 out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%) and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as in ACC cell lines. TERT promoter mutations preferentially occurred in SDH-deficient setting (P=0.01) being present in 3/47 (6.4%) SDH-deficient tumors versus 0/171 (0%) of SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and extra-adrenal PGLs. Additionally, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors.Endocrine Related Cancer 06/2014; 21(4). DOI:10.1530/ERC-13-0429 · 4.91 Impact Factor