Prevalence of promoter mutations in the TERT gene in oral cavity squamous cell carcinoma

Chang, Kai Ping; Wang, Chun-I; Pickering, Curtis R.; Huang, Yen‐Lin; Tsai, Chia-Lung; Tsang, Ngan Ming; Kao, Huang Kai; Cheng, Ming Huei; Myers, Jeffrey N.

doi:10.1002/hed.24728

Cited by 44 publications

(46 citation statements)

References 48 publications

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“…The recent discovery of two activating mutations within the core promoter of the TERT gene prompted the significant role of such genetic event in the development of many cancer types . In the current study, we investigated the presence of TERT promoter mutations in head and neck cancers and confirmed the high rate of hot spot nucleotide changes in oral SCC (60%), particularly in tongue tumours, and the rarity of such mutations in oropharyngeal SCC . The expression level of telomerase was comparable in HPV‐positive and HPV‐negative oropharyngeal SCC suggesting that the low expression of E6 and E7 oncoproteins, previously shown in these tumours, has little effect on the activation of TERT promoter …”

Section: Discussionsupporting

confidence: 61%

Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma

Annunziata

Pezzuto

Greggi

et al. 2018

Intl Journal of Cancer

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Two recurrent mutations (-124 G > A and -146 G > A) in the core promoter region of the human telomerase reverse transcriptase (TERT) gene create consensus binding sites for ETS transcription factors and cause increased TERT expression in several tumour types. We analyzed TERT promoter mutations and TERT mRNA levels in head and neck cancer, cervical carcinoma and cervical intraepithelial neoplasia (CIN) as well as in C-4I, CaSki, HeLa and SiHa cervical cell lines. Nucleotide sequence analysis of TERT promoter region showed that 33.3% of oral squamous cell carcinoma (SCC) and 16.8% of cervical SCC harboured mutually exclusive G to A transitions at nucleotide position -124 or -146. TERT promoter was mutated at nucleotide -146 (G > A) in SiHa cell line. Other nucleotide changes creating in some cases putative ETS binding sites were more frequent in oral SCC (26.7%) than in cervical carcinoma (4.8%). The frequency of mutations was independent of human papillomavirus (HPV) tumour status in both cervical and oral cancer. Expression of TERT gene was significantly higher in TERT promoter mutated (-124G > A or -146G > A) cervical SCC compared to not mutated SCC irrespective of HPV16 E6 and E7 levels. Such hot spot changes were not detected in oropharyngeal SCC, cervical adenocarcinoma and CIN lesions. Our results suggest that TERT promoter mutations play a relevant role in oral SCC as well as in cervical SCC, besides the already known effect of HPV16 E6 protein on TERT expression.

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Section: Discussionsupporting

confidence: 61%

Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma

Annunziata

Pezzuto

Greggi

et al. 2018

Intl Journal of Cancer

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“…Chen et al screened for the DNA integration from a panel of onco-viruses including HPV, EBV, and BKV in different types of tumors, and they did detect the presence of insertion events, but integration breakpoints were located at other cancer-driving genes rather than the TERT locus [67]. However, another recent study showed that HPV DNA targeted the TERT locus for integration in cells and tumors derived from head and neck cancer [82], but more detailed and comprehensive analyses are required.…”

Section: Onco-viral Dna Insertionsmentioning

confidence: 99%

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

2019

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Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres, thereby delaying the onset of the majority of cancer types until post-reproductive age. Indeed, telomerase is silent in most differentiated human cells, predominantly due to the transcriptional repression of its catalytic component telomerase reverse transcriptase (TERT) gene. The lack of telomerase/TERT expression leads to progressive telomere erosion in dividing human cells, whereas critically shortened telomere length induces a permanent growth arrest stage named replicative senescence. TERT/telomerase activation has been experimentally shown to be essential to cellular immortalization and malignant transformation by stabilizing telomere length and erasing the senescence barrier. Consistently, TERT expression/telomerase activity is detectable in up to 90% of human primary cancers. Compelling evidence has also accumulated that TERT contributes to cancer development and progression via multiple activities beyond its canonical telomere-lengthening function. Given these key roles of telomerase and TERT in oncogenesis, great efforts have been made to decipher mechanisms underlying telomerase activation and TERT induction. In the last two decades since the TERT gene and promoter were cloned, the derepression of the TERT gene has been shown to be achieved typically at a transcriptional level through dysregulation of oncogenic factors or signaling, post-transcriptional/translational regulation and genomic amplification. However, advances in high-throughput next-generation sequencing technologies have prompted a revolution in cancer genomics, which leads to the recent discovery that genomic alterations take center stage in activating the TERT gene. In this review article, we summarize critical mechanisms activating TERT transcription, with special emphases on the contribution of TERT promoter mutations and structural alterations at the TERT locus, and briefly discuss the underlying implications of these genomic events-driven TERT hyperactivity in cancer initiation/progression and potential clinical applications as well.

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“…There is a partial overlap of the study populations of Eckel-Passow et al [ 71 ] and Pekmezci et al [ 63 ]; e includes grade I-IV hepatocellular carcinoma and clear cell ( n = 57) [ 107 ] and non-clear cell hepatocellular carcinoma, NOS ( n = 259) [ 107 ]; f includes widely invasive ( n = 126) [ 140 ] and minimaly invasive ( n = 44) [ 140 ] Hürthle cell carcinomas; g these cases were classified according to the AFIP criteria [ 220 ]. It does not seem to exist an overlap of the study populations of Landa et al [ 127 ] and Landa et al [ 133 ]; it may exist an overlap of the study populations of Kim et al [ 136 ] and Kim et al [ 137 ] and the study populations of Melo et al [ 125 ] and Melo et al [ 138 ]; h includes buccal ( n = 84) [ 158 ], gum ( n = 34) [ 158 ], lip ( n = 6) [ 158 ], tongue ( n = 63) [ 158 ], floor of mouth ( n = 22) [ 49 , 158 ], alveolar ridge ( n = 1) [ 49 ], mandibule ( n = 1) [ 49 ], hard palate ( n = 2) [ 49 ], supraglottis ( n = 4) [ 49 ], glottis ( n = 1) [ 49 ], tonsil ( n = 18) [ 49 ], larynx ( n = 2) [ 49 ], oropharynx/hypopharynx ( n = 1) [ 49 ] and hypopharynx ( n = 1) [ 49 ]; i includes pure ( n = 48) [ 49 ] and mixed ( n = 28) [ 180 ] desmoplastic melanoma; j includes cutaneous melanomas, NOS and spitzoid melanocytic neoplasms ( n = 56) [ 183 ], occult melanoma ( n = 34), chronically sun-damaged (CSD) ( n = 18) [ 179 ] and non-CSD melanomas ( n = 12) […”

Section: Figurementioning

confidence: 99%

Telomere Maintenance Mechanisms in Cancer

Gaspar

Sá

Lopes

et al. 2018

Genes

135

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Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from genome-scale studies of major importance. In this review, we address seven different TMMs in tumour cells: mutations of the TERT promoter (TERTp), amplification of the genes TERT and TERC, polymorphic variants of the TERT gene and of its promoter, rearrangements of the TERT gene, epigenetic changes, ALT, and non-defined TMM (NDTMM). We gathered information from over fifty thousand patients reported in 288 papers in the last years. This wide data collection enabled us to portray, by organ/system and histotypes, the prevalence of TERTp mutations, TERT and TERC amplifications, and ALT in human tumours. Based on this information, we discuss the putative future clinical impact of the aforementioned mechanisms on the malignant transformation process in different setups, and provide insights for screening, prognosis, and patient management stratification.

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Prevalence of promoter mutations in the TERT gene in oral cavity squamous cell carcinoma

Cited by 44 publications

References 48 publications

Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma

Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

Telomere Maintenance Mechanisms in Cancer

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