The activating TERT promoter mutation C228T is recurrent in subsets of adrenal tumors

The telomerase reverse transcriptase gene (TERT) encodes the reverse transcriptase component of the telomerase complex, which is essential for telomere stabilization and cell immortalization. Recent studies have demonstrated a transcriptional activation role for theTERTpromoter mutations C228T and C250T in many human cancers, as well as a role in aggressive disease with potential clinical applications. Although telomerase activation is known in adrenal tumors, the underlying mechanisms are not established. We assessed C228T and C250TTERTmutations by direct Sanger sequencing in tumors of the adrenal gland, and further evaluated potential associations with clinical parameters and telomerase activation. A total of 199 tumors were evaluated, including 34 adrenocortical carcinomas (ACC), 47 adrenocortical adenomas (ACA), 105 pheochromocytomas (PCC; ten malignant and 95 benign), and 13 abdominal paragangliomas (PGL; nine malignant and four benign).TERTexpression levels were determined by quantitative RT-PCR. The C228T mutation was detected in 4/34 ACCs (12%), but not in any ACA (P=0.028). C228T was also observed in one benign PCC and in one metastatic PGL. The C250T mutation was not observed in any case. In the ACC and PGL groups,TERTmutation-positive cases exhibitedTERTexpression, indicating telomerase activation; however, since expression was also revealed inTERTWT cases, this could denote additional mechanisms ofTERTactivation. To conclude, theTERTpromoter mutation C228T is a recurrent event associated withTERTexpression in ACCs, but rarely occurs in PGL and PCC. The involvement of theTERTgene in ACC represents a novel mutated gene in this entity.

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Plasma dehydroepiandrosterone sulfate levels in patients with hyperfunctioning and non-hyperfunctioning adrenal tumors before and after adrenal surgery

Acta Endocrinologica ◽

10.1530/eje.0.1360290 ◽

1997 ◽

Vol 136 (3) ◽

pp. 290-295 ◽

Cited By ~ 8

Author(s):

Miklós Tóth ◽

Károly Rácz ◽

Ibolya Varga ◽

Vilmos Adleff ◽

Csilla Jakab ◽

...

Keyword(s):

Normal Subjects ◽

Dehydroepiandrosterone Sulfate ◽

High Plasma ◽

Adrenal Tumors ◽

Adrenal Surgery ◽

Adrenocortical Tumors ◽

Adrenocortical Adenomas ◽

Before And After ◽

Adrenocortical Carcinomas ◽

Glucocorticoid Production

Abstract To investigate the clinical significance of plasma dehydroepiandrosterone sulfate (DHEAS) measurements, 175 patients with histologically confirmed adrenal tumors, 10 cortisol-producing adenomas, 59 aldosterone-producing adenomas, 56 non-hyperfunctioning adenomas, 13 adrenocortical carcinomas, 13 adrenal cysts, and 24 adrenomedullary tumors were studied. Plasma DHEAS levels were expressed as percentage of the mean of sex- and age-matched groups of healthy, normal subjects (DHEAS %). We found that before adrenal surgery, DHEAS % values were significantly reduced in patients with cortisol-producing (mean, 15·2% of control; 95% confidence interval (CI), 9·4–24·7%), non-hyperfunctioning (28·4%; 22·4–36·0% as well as aldosterone-producing adrenocortical adenomas (55·4%; 47·1–65·1%) compared with controls, while values were normal in patients with adrenal cysts and in those with adrenomedullary tumors. Plasma DHEAS % values exhibited a great variability in adrenocortical carcinomas (mean, 84·0%; 95% CI, 33·2–212·5%). Death from adrenocortical carcinoma was more frequent in patients with high plasma DHEAS % values compared with those with low DHEAS %. During long-term postoperative monitoring, we found that plasma DHEAS levels of patients with aldosterone-producing and non-hyperfunctioning adenomas returned to normal in the second and fourth postoperative year respectively. In patients with cortisol-producing adenomas, plasma DHEAS remained suppressed for as long as 8 years after the operation. These findings show that except in adrenocortical carcinomas and cysts, plasma DHEAS levels are significantly decreased in all groups of adrenocortical tumors, including non-hyperfunctioning and aldosteroneproducing tumors. The extent of this decrease and the postoperative persistence of suppressed plasma DHEAS levels may be related to the glucocorticoid production of adrenocortical tumors. European Journal of Endocrinology 136 290–295

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Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia

Endocrine Related Cancer ◽

10.1530/erc-13-0429 ◽

2014 ◽

Vol 21 (4) ◽

pp. 653-661 ◽

Cited By ~ 29

Author(s):

Thomas G Papathomas ◽

Lindsey Oudijk ◽

Ellen C Zwarthoff ◽

Edward Post ◽

Floor A Duijkers ◽

...

Keyword(s):

Adrenal Gland ◽

Reverse Transcriptase ◽

Cell Lines ◽

Preliminary Evidence ◽

Telomerase Reverse Transcriptase ◽

Human Neuroblastoma ◽

Potential Association ◽

Neuroblastic Tumors ◽

Adrenocortical Carcinomas ◽

Promoter Mutations

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 exploreTERTpromoter 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 PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assessTERTpromoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association betweenTERTpromoter mutations and SDH deficiency.TERTpromoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; fourC228Tmutations in 38 ACCs (10.5%), twoC228Tmutations in 18 ea PGLs (11.1%), oneC250Tmutation in 36 GISTs (2.8%), and threeC228Tmutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines.TERTpromoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude thatTERTpromoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition ofTERTpromoter mutations in SDH-deficient tumors.

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Histological scores and tumor size on stage II in adrenocortical carcinomas

Rare Tumors ◽

10.1177/20363613211026494 ◽

2021 ◽

Vol 13 ◽

pp. 203636132110264

Author(s):

Rui Caetano Oliveira ◽

Maria João Martins ◽

Carolina Moreno ◽

Rui Almeida ◽

João Carvalho ◽

...

Keyword(s):

Tumor Size ◽

Correct Diagnosis ◽

Stage Ii ◽

Adrenal Tumors ◽

Median Size ◽

Adrenocortical Adenomas ◽

History Of ◽

Aggressive Tumors ◽

Adrenocortical Carcinomas ◽

Worse Prognosis

Adrenocortical carcinomas (ACC) are aggressive tumors with a poor prognosis. Histological scores are advised for the diagnosis, however, there are borderline cases that may be misjudged as adrenocortical adenomas (ACA). The three main scores used are: Weiss Modified System (WMS), Reticulin Algorithm (RA), and Helsinki Score (HS). We intend to compare the accuracy of the three scores in ACC diagnosis and to identify predictive factors of overall survival (OS). Retrospective study (2004–2016) at Centro Hospitalar e Universitário de Coimbra of the adrenal tumors, classified as ACC or ACA, with a history of posterior tumor relapse/metastases, without lesions in the contralateral adrenal gland: 13F and 6M, with a median age of 51 ± 12.41 years. Nodules’ median size was 9.20 ± 6.2 cm. Patients had a median OS of 52 ± 18.6 months, with 57.9% and 46.3%, at 3 and 5 years. Seven patients had local recurrence and nine had metastases. Thirteen cases were in stage II. The WMS and the HS allowed a diagnosis of ACC in 15 cases and the RA defined ACC in 17 cases. All cases had, at least, focal disruption of the reticulin framework. More than 5 mitosis/50 HPF was associated with worse OS: 49.67 ± 21.43 versus 108.86 ± 14.02 months ( p = 0.026). In patients with stage II, tumor size ⩾10 cm was associated with worse OS: 19.25 ± 7.15 versus 96.11 ± 16.7 months ( p = 0.007), confirmed by multivariate analysis ( p = 0.031). The correct diagnosis of ACC is a pathologist responsibility. The RA seems the most accurate. Any loss of the reticulin framework should raise awareness for malignancy. In patients on stage II, a size ⩾10 cm is a predictor of worse prognosis.

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TERT Copy Number Alterations, Promoter Mutations and Rearrangements in Adrenocortical Carcinomas

Endocrine Pathology ◽

10.1007/s12022-021-09691-0 ◽

2021 ◽

Author(s):

Sounak Gupta ◽

Helen Won ◽

Kalyani Chadalavada ◽

Gouri J. Nanjangud ◽

Ying-Bei Chen ◽

...

Keyword(s):

Copy Number ◽

Adverse Outcomes ◽

The Cancer Genome Atlas ◽

Prognostic Impact ◽

Adrenocortical Adenomas ◽

High Prevalence ◽

Cancer Genome Atlas ◽

Tcga Dataset ◽

Adrenocortical Carcinomas ◽

Promoter Mutations

AbstractMolecular characterization of adrenocortical carcinomas (ACC) by The Cancer Genome Atlas (TCGA) has highlighted a high prevalence of TERT alterations, which are associated with disease progression. Herein, 78 ACC were profiled using a combination of next generation sequencing (n = 76) and FISH (n = 9) to assess for TERT alterations. This data was combined with TCGA dataset (n = 91). A subset of borderline adrenocortical tumors (n = 5) and adrenocortical adenomas (n = 7) were also evaluated. The most common alteration involving the TERT gene involved gains/amplifications, seen in 22.2% (37/167) of cases. In contrast, “hotspot” promoter mutations (C > T promoter mutation at position -124, 7/167 cases, 4.2%) and promoter rearrangements (2/165, 1.2%) were rare. Recurrent co-alterations included 22q copy number losses seen in 24% (9/38) of cases. Although no significant differences were identified in cases with and without TERT alterations pertaining to age at presentation, tumor size, weight, laterality, mitotic index and Ki67 labeling, cases with TERT alterations showed worse outcomes. Metastatic behavior was seen in 70% (28/40) of cases with TERT alterations compared to 51.2% (65/127, p = 0.04) of cases that lacked these alterations. Two (of 5) borderline tumors showed amplifications and no TERT alterations were identified in 7 adenomas. In the borderline group, 0 (of 4) patients with available follow up had adverse outcomes. We found that TERT alterations in ACC predominantly involve gene amplifications, with a smaller subset harboring “hotspot” promoter mutations and rearrangements, and 70% of TERT-altered tumors are associated with metastases. Prospective studies are needed to validate the prognostic impact of these findings.

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Editorial Comment from Dr Urabe to Telomerase reverse transcriptase promoter mutation in tumorigenesis of bladder cancer: Evolutionary trajectory by algorithmic inference from cross‐sectional data

International Journal of Urology ◽

10.1111/iju.14580 ◽

2021 ◽

Author(s):

Fumihiko Urabe

Keyword(s):

Bladder Cancer ◽

Editorial Comment ◽

Reverse Transcriptase ◽

Telomerase Reverse Transcriptase ◽

Promoter Mutation ◽

Cross Sectional ◽

Evolutionary Trajectory

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The role of telomerase reverse transcriptase (TERT) promoter mutations in prognosis in bladder cancer

Bioengineered ◽

10.1080/21655979.2021.1915725 ◽

2021 ◽

Vol 12 (1) ◽

pp. 1495-1504

Author(s):

Song Wan ◽

Xuan Liu ◽

Wei Hua ◽

Ming Xi ◽

Yulin Zhou ◽

...

Keyword(s):

Bladder Cancer ◽

Reverse Transcriptase ◽

Telomerase Reverse Transcriptase ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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Editorial Comment from Dr Kurobe to Telomerase reverse transcriptase promoter mutation in tumorigenesis of bladder cancer: Evolutionary trajectory by algorithmic inference from cross‐sectional data

International Journal of Urology ◽

10.1111/iju.14594 ◽

2021 ◽

Author(s):

Masahiro Kurobe

Keyword(s):

Bladder Cancer ◽

Editorial Comment ◽

Reverse Transcriptase ◽

Telomerase Reverse Transcriptase ◽

Promoter Mutation ◽

Cross Sectional ◽

Evolutionary Trajectory

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Myc and Human Papillomavirus Type 16 E7 Genes Cooperate To Immortalize Human Keratinocytes

Journal of Virology ◽

10.1128/jvi.00669-07 ◽

2007 ◽

Vol 81 (22) ◽

pp. 12689-12695 ◽

Cited By ~ 27

Author(s):

Xuefeng Liu ◽

Gary L. Disbrow ◽

Hang Yuan ◽

Vjekoslav Tomaić ◽

Richard Schlegel

Keyword(s):

Transcriptional Activation ◽

High Efficiency ◽

P53 Protein ◽

Significant Proportion ◽

Telomerase Activity ◽

Human Papillomaviruses ◽

Mrna Levels ◽

Crisis Period ◽

Cell Immortalization ◽

Immortalized Cells

ABSTRACT The E6 protein of the oncogenic human papillomaviruses (HPVs), in combination with the E7 protein, is essential for the efficient immortalization of human foreskin keratinocytes (HFKs). Since we recently demonstrated that E6 activates the human telomerase reverse transcriptase (hTERT) promoter via a Myc-dependent mechanism, we speculated that overexpressed Myc might be able to substitute for E6 in cell immortalization. Myc (similar to E6) was unable to immortalize HFKs when transduced alone, despite inducing high levels of telomerase activity. However, when transduced with E7, Myc immortalized HFKs following a brief but detectable crisis period. In contrast to E6 + E7-immortalized cells, the Myc + E7-immortalized cells expressed high levels of p53 protein as well as two p53-regulated proteins, p21 and hdm-2. The increase in p21 and hdm-2 proteins correlated directly with their mRNA levels, suggesting transcriptional activation of the respective genes by the overexpressed p53 protein. Interestingly, a significant proportion of the p53 protein in the Myc + E7-immortalized cells was localized to the cytoplasm, potentially due to interactions with the overexpressed hdm-2 protein. Regardless, cell immortalization by the Myc + E7 genes occurred independently of p53 degradation. Since we have already observed high-efficiency cell immortalization with the hTERT + E7 or E6 mutant (p53 degradation-defective) + E7 genes (i.e., no crisis period) that proceeds in the presence of high levels of p53, we hypothesize that the crisis period in the Myc + E7 cells is due not to the levels of the p53 protein but rather to unique properties of the Myc protein. The common factor in cell immortalization by the three gene sets (E6 + E7, Myc + E7, and hTERT + E7 genes) is the induction of telomerase activity.

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Suppressors of Saccharomyces cerevisiae his3 promoter mutations lacking the upstream element

Molecular and Cellular Biology ◽

10.1128/mcb.5.8.1901-1909.1985 ◽

1985 ◽

Vol 5 (8) ◽

pp. 1901-1909

Author(s):

M A Oettinger ◽

K Struhl

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcriptional Activation ◽

Tata Box ◽

Micrococcal Nuclease ◽

Promoter Element ◽

Wild Type ◽

Upstream Promoter ◽

In The Wild ◽

Promoter Mutations ◽

His3 Gene

Transcription of the Saccharomyces cerevisiae his3 gene requires an upstream promoter element and a TATA element. A strain containing his3-delta 13, an allele which deletes the upstream promoter element but contains the TATA box and intact structural gene, fails to express the gene and consequently is unable to grow in medium lacking histidine. In this paper we characterize His+ revertants of his3-delta 13 which are due to unlinked suppressor mutations. Recessive suppressors in three different ope genes allow his3-delta 13 to be expressed at wild-type levels. In all cases, the suppression is due to increased his3 transcription. However, unlike the wild-type his3 gene, whose transcripts are initiated about equally from two different sites (+1 and +12), transcription due to the ope mutations is initiated only from the +12 site, ope-mediated transcription is regulated in a novel manner; it is observed in minimal medium, but not in rich broth. Although ope mutations restore wild-type levels of transcription, his3 chromatin structure, as assayed by micrococcal nuclease sensitivity of the TATA box, resembles that found in the his3-delta 13 parent rather than in the wild-type strain. This provides further evidence that TATA box sensitivity is not correlated with transcriptional activation. ope mutations are pleiotropic in that cells have a crunchy colony morphology and lyse at 37 degrees C in conditions of normal osmolarity. ope mutations are allele specific because they fail to suppress five other his3 promoter mutations. We discuss implications concerning upstream promoter elements and propose some models for ope suppression.

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