Highly prevalent TERT promoter mutations in aggressive thyroid cancers
TL;DR: For the first time, to the authors' knowledge, TERT promoter mutations in thyroid cancers are demonstrated, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.
Abstract: Mutations 1 295 228 C>T and 1 295 250 C>T (termed C228T and C250T respectively), corresponding to −124 C>T and −146 C>T from the translation start site in the promoter of the telomerase reverse transcriptase (TERT) gene, have recently been reported in human cancers, but not in thyroid cancers yet. We explored these mutations in thyroid cancers by genomic sequencing of a large number of primary tumor samples. We found the C228T mutation in 0 of 85 (0.0%) benign thyroid tumors, 30 of 257 (11.7%) papillary thyroid cancers (PTC), 9 of 79 (11.4%) follicular thyroid cancers (FTC), 3 of 8 (37.5%) poorly differentiated thyroid cancers (PDTC), 23 of 54 (42.6%) anaplastic thyroid cancers (ATC), and 8 of 12 (66.7%) thyroid cancer cell lines. The C250T mutation was uncommon, but mutually exclusive with the C228T mutation, and the two mutations were collectively found in 11 of 79 (13.9%) FTC, 25 of 54 (46.3%) ATC, and 11 of 12 (91.7%) thyroid cancer cell lines. Among PTC variants, the C228T mutation was found in 4 of 13 (30.8%) tall-cell PTC (TCPTC), 23 of 187 (12.3%) conventional PTC, and 2 of 56 (3.6%) follicular variant PTC samples. No TERT mutation was found in 16 medullary thyroid cancer samples. The C228T mutation was associated with the BRAF V600E mutation in PTC, being present in 19 of 104 (18.3%) BRAF mutation-positive PTC vs 11 of 153 (7.2%) the BRAF mutation-negative PTC samples (P=0.0094). Conversely, BRAF mutation was found in 19 of 30 (63.3%) C228T mutation-positive PTC vs 85 of 227 (37.4%) C228T mutation-negative PTC samples (P=0.0094). We thus for the first time, to our knowledge, demonstrate TERT promoter mutations in thyroid cancers, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.
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University of Colorado Boulder1, Harvard University2, Mayo Clinic3, Boston University4, University of Pennsylvania5, University of Pittsburgh6, University of Siena7, University Health Network8, Institut Gustave Roussy9, Oregon Health & Science University10, University of Texas MD Anderson Cancer Center11, Duke University12, University of Cincinnati13, Memorial Sloan Kettering Cancer Center14, MedStar Washington Hospital Center15
TL;DR: Evidence-based recommendations are developed to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer and represent, in the authors' opinion, contemporary optimal care for patients with these disorders.
Abstract: Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. Methods: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Gr...
10,501 citations
Cites background from "Highly prevalent TERT promoter muta..."
...In some (154;579), but not all (580) reports, TERT mutations were found more often in PTC carrying a BRAF mutation....
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TL;DR: These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance.
Abstract: BACKGROUND. Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization.
METHODS. We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC).
RESULTS. Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation.
CONCLUSIONS. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality.
FUNDING. This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-{"type":"entrez-nucleotide","attrs":{"text":"CA160001","term_id":"35072944","term_text":"CA160001"}}CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.
730 citations
TL;DR: As in many cancers, genetic analysis of thyroid cancers has identified subgroups that differ in their pathogenesis and has defined targets that make the cancer susceptible to particular therapies.
Abstract: As in many cancers, genetic analysis of thyroid cancers has identified subgroups that differ in their pathogenesis and has defined targets that make the cancer susceptible to particular therapies. Recent progress leading to new treatments is reviewed.
613 citations
TL;DR: Coexisting BRAF V600E and TERT C228T mutations form a novel genetic background that defines PTC with the worst clinicopathologic outcomes, providing unique prognostic and therapeutic implications.
Abstract: Purpose To investigate the prognostic value of the BRAF V600E mutation and the recently identified TERT promoter mutation chr5:1,295,228C>T (C228T), individually and in their coexistence, in papillary thyroid cancer (PTC). Patients and Methods We performed a retrospective study of the relationship of BRAF and TERT C228T mutations with clinicopathologic outcomes of PTC in 507 patients (365 women and 142 men) age 45.9 ± 14.0 years (mean ± SD) with a median follow-up of 24 months (interquartile range, 8 to 78 months). Results Coexisting BRAF V600E and TERT C228T mutations were more commonly associated with high-risk clinicopathologic characteristics of PTC than they were individually. Tumor recurrence rates were 25.8% (50 of 194;77.60 recurrences per 1,000 person-years; 95% CI, 58.81 to 102.38) versus 9.6% (30 of 313; 22.88 recurrences per 1,000 person-years; 95% CI, 16.00 to 32.72) in BRAF mutation–positive versus –negative patients (hazard ratio [HR], 3.22; 95% CI, 2.05 to 5.07) and 47.5% (29 of 61; 108.55...
526 citations
TL;DR: Key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents are revealed.
Abstract: Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.
447 citations
Cites background from "Highly prevalent TERT promoter muta..."
...Thyroid cancer (papillary and poorly differentiated carcinomas) 50–52 [105]...
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References
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TL;DR: A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination, and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake.
Abstract: The global burden of cancer continues to increase largely because of the aging and growth of the world population alongside an increasing adoption of cancer-causing behaviors, particularly smoking, in economically developing countries. Based on the GLOBOCAN 2008 estimates, about 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world. Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females, accounting for 23% of the total cancer cases and 14% of the cancer deaths. Lung cancer is the leading cancer site in males, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. Breast cancer is now also the leading cause of cancer death among females in economically developing countries, a shift from the previous decade during which the most common cause of cancer death was cervical cancer. Further, the mortality burden for lung cancer among females in developing countries is as high as the burden for cervical cancer, with each accounting for 11% of the total female cancer deaths. Although overall cancer incidence rates in the developing world are half those seen in the developed world in both sexes, the overall cancer mortality rates are generally similar. Cancer survival tends to be poorer in developing countries, most likely because of a combination of a late stage at diagnosis and limited access to timely and standard treatment. A substantial proportion of the worldwide burden of cancer could be prevented through the application of existing cancer control knowledge and by implementing programs for tobacco control, vaccination (for liver and cervical cancers), and early detection and treatment, as well as public health campaigns promoting physical activity and a healthier dietary intake. Clinicians, public health professionals, and policy makers can play an active role in accelerating the application of such interventions globally.
52,293 citations
TL;DR: BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers, with a single substitution (V599E) accounting for 80%.
Abstract: Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.
9,785 citations
"Highly prevalent TERT promoter muta..." refers background in this paper
...Melanomas and follicular cell-derived thyroid cancer share considerably similar genetic backgrounds; for example, they both harbor the BRAF V600E mutation with a high prevalence (Davies et al. 2002, Xing 2005a)....
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TL;DR: Two independent mutations within the core promoter of telomerase reverse transcriptase (TERT) are described, which collectively occur in 50 of 70 melanomas examined, suggesting somatic mutations in regulatory regions of the genome may represent an important tumorigenic mechanism.
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 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.
1,602 citations
TL;DR: A melanoma-prone family through linkage analysis and high-throughput sequencing was investigated and a disease-segregating germline mutation in the promoter of the telomerase reverse transcriptase (TERT) gene, which encodes the catalytic subunit of telomersase, caused up to twofold increase in transcription.
Abstract: Cutaneous melanoma occurs in both familial and sporadic forms. We investigated a melanoma-prone family through linkage analysis and high-throughput sequencing and identified a disease-segregating germline mutation in the promoter of the telomerase reverse transcriptase (TERT) gene, which encodes the catalytic subunit of telomerase. The mutation creates a new binding motif for Ets transcription factors and ternary complex factors (TCFs) near the transcription start and, in reporter gene assays, caused up to twofold increase in transcription. We then screened the TERT promoter in sporadic melanoma and observed recurrent ultraviolet signature somatic mutations in 125 of 168 (74%) of human cell lines derived from metastatic melanomas, 45 of 53 corresponding metastatic tumor tissues (85%), and 25 of 77 (33%) primary melanomas. The majority of those mutations occurred at two positions in the TERT promoter and also generated binding motifs for Ets/TCF transcription factors.
1,557 citations
"Highly prevalent TERT promoter muta..." refers background or result in this paper
...A germline AOC (TOG on opposite strand) mutation at K57 bp from the ATG translation start site of the TERT gene was found in familial melanomas (Horn et al. 2013), but we did not find this mutation in any of the thyroid tumor samples or cell lines in the present study....
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...…extremely high in thyroid cancer cell lines (91.7%), which is in contrast to the low prevalence of 16% (24/150) in general cancer cell lines from the Cancer Cell Line Encyclopedia (Huang et al. 2013), but is similar to the high prevalence of 74% (125/168) in melanoma cell lines (Horn et al. 2013)....
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...In fact, the two mutations have been demonstrated to confer increased transcriptional activity on the TERT promoter (Horn et al. 2013, Huang et al. 2013)....
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...…cancer; MTC, medullary thyroid cancer. http://erc.endocrinology-journals.org q 2013 Society for Endocrinology DOI: 10.1530/ERC-13-0210 Printed in Great Britain UACC62) examined harbored the C250T mutation (data not shown), as found in other melanoma cell lines (Horn et al. 2013, Huang et al. 2013)....
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...This resulted in a PCR product of 235 bp, containing the sites where mutations C228T and C250T occur in melanomas (Horn et al. 2013, Huang et al. 2013)....
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01 Jan 2012
1,426 citations
"Highly prevalent TERT promoter muta..." refers background in this paper
...R e la te d C a n ce r http://erc.endocrinology-journals.org q 2013 Society for Endocrinology DOI: 10.1530/ERC-13-0210 Printed in Great Britain 40–50 ng of genomic DNA were used in the PCR, which was carried out with an initial denaturation step at 95 8C for 3 min, followed by ten cycles of 95 8C denaturation for 30 s, 55 8C annealing for 30 s, and 68 8C elongation for 1 min....
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...Follicular cell-derived thyroid cancer can be classified into several histological types (DeLellis et al. 2004), among which the most common types are papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), which account for 85–90% and 10–15% of all the thyroid cancers respectively (DeLellis et al. 2004, Jemal et al. 2011, http://erc.endocrinology-journals.org q 2013 Society for Endocrinology DOI: 10.1530/ERC-13-0210 Printed in Great Britain Howlader et al. 2012)....
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...R e la te d C a n ce r http://erc.endocrinology-journals.org q 2013 Society for Endocrinology DOI: 10.1530/ERC-13-0210 Printed in Great Britain Published by Bioscientifica Ltd. Downloa Mutations 1 295 228 COT and 1 295 250 COT (termed C228T and C250T respectively), corresponding to K124 COT and K146 COT from the translation start site in the promoter of the telomerase reverse transcriptase (TERT ) gene, have recently been reported in human cancers, but not in thyroid cancers yet....
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...(doi:10.1016/ j.molmed.2012.11.006) Smallridge RC, Ain KB, Asa SL, Bible KC, Brierley JD, Burman KD, Kebebew E, Lee NY, Nikiforov YE, Rosenthal MS et al. 2012 American Thyroid http://erc.endocrinology-journals.org q 2013 Society for Endocrinology DOI: 10.1530/ERC-13-0210 Printed in Great Britain Association Anaplastic Thyroid Cancer Guidelines Taskforce....
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...Three melanoma cell lines (M14, A375, and PTC, papillary thyroid cancer; CPTC, conventional PTC; FVPTC, follicular variant PTC; TCPTC, tall-cell PTC; FTC, follicular thyroid cancer; DTC, differentiated thyroid cancer (combination of PTC and FTC); PDTC, poorly DTC; ATC, anaplastic thyroid cancer; MTC, medullary thyroid cancer. http://erc.endocrinology-journals.org q 2013 Society for Endocrinology DOI: 10.1530/ERC-13-0210 Printed in Great Britain UACC62) examined harbored the C250T mutation (data not shown), as found in other melanoma cell lines (Horn et al. 2013, Huang et al. 2013)....
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