scholarly journals Clinical Application of TERT Promoter Mutations in Urothelial Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Yujiro Hayashi ◽  
Kazutoshi Fujita ◽  
George J. Netto ◽  
Norio Nonomura
Keyword(s):  
Urothelial Carcinoma ◽  
Replicative Senescence ◽  
Strong Association ◽  
Disease Recurrence ◽  
Telomerase Activity ◽  
High Rate ◽  
Promoter Mutation ◽  
Future Direction ◽  
Promoter Mutations ◽  
Clinical Potential

Urothelial carcinoma (UC) is a common urological malignancy with a high rate of disease recurrence. Telomerase activity, a hallmark of cancer characterized by overcoming the replicative senescence, is upregulated in over 90% of patients with UC. Somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) are frequently detected in UC, and drive telomerase activity. Recent studies have demonstrated a strong association between TERT promoter mutation and tumorigenesis of UC. Also, TERT promoter mutation has great potential for diagnosis, as well as prognosis in UC treatment, and this is also applicable for the liquid biopsy techniques. In this review, we discuss the progress in these areas and highlight the challenges, clinical potential, and future direction for developing UC treatment methods.

Cell-free tumor DNA and TERT promoter mutations in bladder cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 353-353 ◽  
Author(s):  
Franklin W. Huang ◽  
Mikael L. Rinne ◽  
Kevin T. Lundgren ◽  
Stephanie Anne Mullane ◽  
Irene Moreno ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Metastatic Disease ◽  
Tert Promoter Mutation ◽  
Plasma Samples ◽  
Promoter Mutation ◽  
Library Construction ◽  
Non Invasive ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Promoter Mutations

353 Background: Currently, there are no FDA-approved blood biomarkers for the prognosis or prediction of outcomes in urothelial carcinoma (UC). The telomerase reverse transcriptase ( TERT) promoter is recurrently mutated at high frequency in UC (50%). These mutations have been correlated with tumor recurrence and survival. Tumor cell-free DNA (cfDNA) with somatic genomic alterations can be found in the plasma of cancer patients and has the potential for use as a non-invasive cancer biomarker. Detection of TERT promoter mutations in cfDNA might be used as a prognostic tool to monitor disease outcome in UC patients. We set out to detect tumor cfDNA and TERT promoter mutations in cfDNA from patients with UC at different stages. Methods: UC patients receiving chemotherapy in the neoadjuvant, first or second-line metastatic setting had blood collected either before or during therapy. cfDNA was isolated from ~1ml plasma samples using the QIAmp (Qiagen) kit. Samples underwent ultra-low pass whole genome sequencing (ULP-WGS) to determine whether tumor cfDNA could be detected in these samples. TERT promoter mutations were detected using a sensitive qPCR assay. Results: 40 plasma samples from a total of 32 patients with urothelial carcinoma were analyzed. Sufficient amounts of plasma cfDNA were obtained for library construction and ULP-WGS in 11 patients. 6 of these 11 patients were determined to be positive for detectable tumor cfDNA and of these, all were metastatic and 50% (3/6) were positive for a TERT promoter mutation. In total, 8 out of 40 samples (20%) were positive for a TERT promoter mutation, including samples from two patients where total cfDNA yield was insufficient for library construction. A total of ~20% of patients with metastatic disease were positive for TERT promoter mutations in cfDNA. The low percentage of samples having sufficient cfDNA most likely reflects the low volume of plasma used. Conclusions: TERT promoter mutations were identified in cfDNA of UC patients. ULP-WGS showed tumor cfDNA in patients with a high tumor burden and metastatic disease. TERTpromoter mutations in cfDNA could potentially be used as a non-invasive method for detection of disease. These results have implications for the use of cfDNA in the evaluation of advanced UC.

scholarly journals Telomerase and Telomeres Biology in Thyroid Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 2887 ◽  
Author(s):  
Benedetta Donati ◽  
Alessia Ciarrocchi
Keyword(s):  
Current Knowledge ◽  
Telomerase Activity ◽  
High Rate ◽  
Cancer Therapies ◽  
Telomerase Inhibitors ◽  
Tert Promoter ◽  
Tert Promoter Mutations ◽  
Telomere Regulation ◽  
Promoter Mutations

Telomere and telomerase regulation contributes to the onset and evolution of several tumors, including highly aggressive thyroid cancers (TCs). TCs are the most common endocrine malignancies and are generally characterized by a high rate of curability. However, a small but significant percentage develops distant metastasis or progresses into undifferentiated forms associated with bad prognosis and for which poor therapeutic options are available. Mutations in telomerase reverse transcriptase (TERT) promoter are among the most credited prognostic marker of aggressiveness in TCs. Indeed, their frequency progressively increases passing from indolent lesions to aggressive and anaplastic forms. TERT promoter mutations create binding sites for transcription factors, increasing TERT expression and telomerase activity. Furthermore, aggressiveness of TCs is associated with TERT locus amplification. These data encourage investigating telomerase regulating pathways as relevant drivers of TC development and progression to foster the identification of new therapeutics targets. Here, we summarize the current knowledge about telomere regulation and TCs, exploring both canonical and less conventional pathways. We discuss the possible role of telomere homeostasis in mediating response to cancer therapies and the possibility of using epigenetic drugs to re-evaluate the use of telomerase inhibitors. Combined treatments could be of support to currently used therapies still presenting weaknesses.

scholarly journals CSIG-24. GABP LINKS AMPK SIGNALING TO TERT REGULATION IN A TERT PROMOTER MUTATION DEPENDENT MANNER

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi49-vi49
Author(s):  
Andrew McKinney ◽  
Alexandra Amen ◽  
Nicholas Stevers ◽  
Joseph Costello
Keyword(s):  
Replicative Senescence ◽  
Specific Binding ◽  
Telomerase Activity ◽  
Normal Brain ◽  
Dependent Manner ◽  
Tert Promoter Mutation ◽  
Promoter Mutation ◽  
Ampk Signaling ◽  
Tert Promoter ◽  
Wide Range

Abstract Over 90% of human tumors achieve immortality by reactivating telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase. Two mutually exclusive, heterozygous mutations that activate the TERT promoter (TERTp) occur in a wide range of cancers including ~80% of glioblastomas (GBM). The mutations and TERTp activation enable cells to avoid replicative senescence and continue to divide beyond the normal limits on cellular lifespan, thus becoming immortal. Our lab has demonstrated that each mutation creates a novel E26-transformation specific binding site that allows the tetrameric form of the GA-binding protein GABP to bind and aberrantly activate the mutant TERTp. We further showed that reducing a tetramer-forming subunit of GABP, the GABPB1L transactivating subunit, reverses cellular immortality in vitro and reduces tumor growth in vivo. Beyond GABP, little is known about pathways that contribute to immortality via activation of the mutant TERTp. The heterotrimeric 5’ AMP-activated protein kinase (AMPK) complex is activated in human GBM compared to normal brain, and was previously implicated in regulating GABP expression. Here, we have determined that AMPK inhibition decreases transcription of both subunits of the tetrameric GABP complex (GABPA and GABPB1L) in GBM cells, and is sufficient to reduce TERT expression and telomerase activity in a TERT promoter mutation dependent manner. Together, these data suggest a novel and targetable connection between the AMPK signaling axis, telomerase activity and potentially tumor cell immortality.

scholarly journals TERT biology and function in cancer: beyond immortalisation

2017 ◽  
Vol 58 (2) ◽  
pp. R129-R146 ◽  
Author(s):  
Ana Pestana ◽  
João Vinagre ◽  
Manuel Sobrinho-Simões ◽  
Paula Soares
Keyword(s):  
Replicative Senescence ◽  
Tumour Size ◽  
Distant Metastases ◽  
Telomerase Activity ◽  
Response To Treatment ◽  
Malignant Tumours ◽  
Prognostic Features ◽  
And Function ◽  
Transcriptional Reactivation ◽  
Promoter Mutations

Evasion of replicative senescence and proliferation without restriction, sometimes designated as immortalisation, is one of the hallmarks of cancer that may be attained through reactivation of telomerase in somatic cells. In contrast to most normal cells in which there is lack of telomerase activity, upregulation ofTERTtranscription/activity is detected in 80–90% of malignant tumours. In several types of cancer, there is a relationship between the presence ofTERTpromoter mutations,TERTmRNA expression and clinicopathological features, but the biological bridge between the occurrence ofTERTpromoter mutations and the aggressive/invasive features displayed by the tumours remains unidentified. We and others have associated the presence ofTERTpromoter mutations with metastisation/survival in several types of cancer. In follicular cell-derived thyroid cancer, such mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage) as well as with distant metastases, worse response to treatment and poorer survival. In this review, we analyse the data reported in several studies that implyTERTtranscription reactivation/activity with cell proliferation, tumour invasion and metastisation. A particular attention is given to the putative connections betweenTERTtranscriptional reactivation and signalling pathways frequently altered in cancer, such as c-MYC, NF-κB and B-Catenin.

scholarly journals Rectal metastasis from bladder urothelial carcinoma: a case report

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yuki Ii ◽  
Shinya Munakata ◽  
Kumpei Honjo ◽  
Masaya Kawai ◽  
Shingo Kawano ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Tumor Resection ◽  
Disease Recurrence ◽  
Small Areas ◽  
Metastatic Urothelial Carcinoma ◽  
Rare Site ◽  
Difficult Defecation ◽  
Carcinoma Of The Bladder ◽  
Transitional Cells ◽  
Rectal Metastasis

Abstract Background Urothelial carcinoma arises from transitional cells in the urothelial tract. In advanced cases, it can metastasize locally to surrounding organs or distally to organs such as the lungs, bones, or liver. Here we describe a case of rectal metastasis from urothelial carcinoma treated with multiple sessions of transurethral resection of bladder tumor (TURBT). Case presentation A 72-year-old woman presented to our department with abdominal bloating andobstructed defecation. She had undergone two sessions of TURBT for early urothelial carcinoma in another hospital at 64 and 65 months ago, respectively. Cystoscopy at 3 months after the second TURBT session had indicated disease recurrence, and thus, she had been referred to our hospital for further examination, followed by TURBT for the third time at 59 months ago and for the fourth time at 48 months ago; thereafter, she had been followed up with cystoscopy every 6 months without any recurrence. However, she returned to our hospital, complaining of difficult defecation. Subsequent colonoscopy demonstrated an obstructive tumor in the rectum, which was pathologically diagnosed as metastatic urothelial carcinoma of the bladder. Laparoscopic examination revealed two small areas of peritoneal dissemination in the pelvis. A sigmoid colostomy was performed without rectal tumor resection. She has been receiving chemotherapy and is still alive 10 months after surgery. Conclusions Rectal metastasis is a rare site of metastasis for urothelial carcinomas. It is important to consider the possibility of annular rectal constriction caused by infiltrating or metastasizing urothelial carcinoma when managing patients with urothelial carcinoma and with difficult defecation.

scholarly journals Calcitriol Promotes Differentiation of Glioma Stem-Like Cells and Increases Their Susceptibility to Temozolomide

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3577
Author(s):  
Julia Gerstmeier ◽  
Anna-Lena Possmayer ◽  
Süleyman Bozkurt ◽  
Marina E. Hoffmann ◽  
Ivan Dikic ◽  
...  
Keyword(s):  
Vitamin D3 ◽  
Ex Vivo ◽  
Active Form ◽  
Treatment Resistance ◽  
Serum Levels ◽  
Disease Recurrence ◽  
Primary Brain Tumor ◽  
High Rate ◽  
Therapeutic Doses

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor, with a very high rate of recurrence and a median survival of 15 months after diagnosis. Abundant evidence suggests that a certain sub-population of cancer cells harbors a stem-like phenotype and is likely responsible for disease recurrence, treatment resistance and potentially even for the infiltrative growth of GBM. GBM incidence has been negatively correlated with the serum levels of 25-hydroxy-vitamin D3, while the low pH within tumors has been shown to promote the expression of the vitamin D3-degrading enzyme 24-hydroxylase, encoded by the CYP24A1 gene. Therefore, we hypothesized that calcitriol can specifically target stem-like glioblastoma cells and induce their differentiation. Here, we show, using in vitro limiting dilution assays, quantitative real-time PCR, quantitative proteomics and ex vivo adult organotypic brain slice transplantation cultures, that therapeutic doses of calcitriol, the hormonally active form of vitamin D3, reduce stemness to varying extents in a panel of investigated GSC lines, and that it effectively hinders tumor growth of responding GSCs ex vivo. We further show that calcitriol synergizes with Temozolomide ex vivo to completely eliminate some GSC tumors. These findings indicate that calcitriol carries potential as an adjuvant therapy for a subgroup of GBM patients and should be analyzed in more detail in follow-up studies.

A STUDY ON EXPRESSION PROFILE OF BASAL MARKER CD44 AND LUMINAL MARKER CK20 IN UROTHELIAL NEOPLASM AND ITS CORRELATION WITH WHO GRADING AND STAGING OF TUMOUR

2021 ◽  
pp. 29-32
Author(s):  
Krishnendubikas Bag ◽  
Anish kumar Rakshit ◽  
Gopinath Barui
Keyword(s):  
Urothelial Carcinoma ◽  
West Bengal ◽  
Strong Association ◽  
Lower Grade ◽  
Tumour Grade ◽  
Cross Sectional ◽  
Over Expression ◽  
Medical College ◽  
Basal Marker ◽  
Luminal Marker

Aim: Histomorphological study of urothelial carcinoma on TRBT and Cystectomy specimen and its categorization on the basis of WHO grading & pTNM staging and to nd out the correlation between CK20 and CD44 exprression with tumour grade, pTNM staging. Material And Method: This descriptive cross sectional prospective study was conducted in the Department of Pathology, R G Kar Medical College & Hospital Kolkata in collaboration with Department of Urosurgery, R G Kar Medical College & Hospital, Kolkata, West Bengal. The present study is intended to nd out over expression of CD44 & CK20 in Urothelial Carcinoma of Bladder and correlate with tumour grade and clinical features. Result: There is strong association between CD44, CK20 expression and Stage of Urothelial Carcinoma cases and had a strong association between CD44 expressions and grade Urothelial Carcinoma cases. Conclusion: CK20 overexpression was seen more signicantly in High Grade tumours HGPUC (p < 0.05) as well as advanced stage pT2 and CD44 overexpression was more signicantly in lower grade tumours LGPUC (p<0.05) as well as lower stages pT1 in urothelial carcinoma. An inverse relasionship was noted in the staining patterns of CK20 and CD44 within individual cases as well as aggregate data,with (68.24%) of tumours with CD44 loss showing CK20 positivity.

1780 FEMALE GENDER IS ASSOCIATED WITH HIGHER RISK OF DISEASE RECURRENCE IN PATIENTS WITH PRIMARY T1 HIGH GRADE UROTHELIAL CARCINOMA OF THE BLADDER

2013 ◽  
Vol 189 (4S) ◽  
Author(s):  
Luis A Kluth ◽  
Harun Fajkovic ◽  
Evanguelos Xylinas ◽  
Joseph J Crivelli ◽  
Niccolo Passoni ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Female Gender ◽  
Disease Recurrence ◽  
High Grade ◽  
Risk Of Disease ◽  
Carcinoma Of The Bladder

scholarly journals Cisplatin-induced apoptotic endonuclease EndoG inhibits telomerase activity and causes malignant transformation of human CD4+ T lymphocytes

2017 ◽  
Vol 63 (1) ◽  
pp. 13-26 ◽  
Author(s):  
D.D. Zhdanov ◽  
D.A. Vasina ◽  
E.V. Orlova ◽  
V.S. Orlova ◽  
V.S. Pokrovsky ◽  
...  
Keyword(s):  
T Cells ◽  
Alternative Splicing ◽  
Malignant Transformation ◽  
Cd4 T Cells ◽  
Replicative Senescence ◽  
Telomerase Activity ◽  
Full Length ◽  
Leukemic Cells ◽  
Proliferative Potential ◽  
Human Telomerase Reverse Transcriptase

Alternative splicing of telomerase catalytic subunit hTERT pre-mRNA (human Telomerase Reverse Transcriptase) regulates telomerase activity. Increased expression of non-active splice variant hTERT results in inhibition of telomerase. Apoptotic endonuclease EndoG is known to participate in hTERT alternative splicing. Expression of EndoG can be induced in response to DNA damages. The aim of this study was to determine the ability of a DNA-damaging compound, cisplatin, to induce EndoG and its influence on alternative splicing of hTERT and telomerase activity in human CD4+ Т lymphocytes. Overexpression of EndoG in CD4+ T cells downregulated the expression of active full-length hTERT variant and upregulated its non-active spliced variant. Reduction of full-length hTERT caused downregulation of telomerase activity, shortening of telomeres length during cell divisions, converting cells to the replicative senescence state, activation of apoptosis and finally cell death. Few cells survived and underwent malignant transformation. Transformed cells have increased telomerase activity and proliferative potential compare to initial CD4+ T cells. These cells have phenotype of T lymphoblastic leukemic cells and are able to form tumors and cause death in experimental mice.

Epigenetic features in regulation of telomeres and telomerase in stem cells

2021 ◽  
Author(s):  
Fatma Dogan ◽  
Nicholas R. Forsyth
Keyword(s):  
Stem Cells ◽  
Telomere Length ◽  
Cell Biology ◽  
Replicative Senescence ◽  
Telomerase Activity ◽  
Cell Phenotype ◽  
Tissue Degeneration ◽  
Unique System ◽  
Telomerase Regulation

The epigenetic nature of telomeres is still controversial and different human cell lines might show diverse histone marks at telomeres. Epigenetic modifications regulate telomere length and telomerase activity that influence telomere structure and maintenance. Telomerase is responsible for telomere elongation and maintenance and is minimally composed of the catalytic protein component, telomerase reverse transcriptase (TERT) and template forming RNA component, telomerase RNA (TERC). TERT promoter mutations may underpin some telomerase activation but regulation of the gene is not completely understood due to the complex interplay of epigenetic, transcriptional, and posttranscriptional modifications. Pluripotent stem cells (PSCs) can maintain an indefinite, immortal, proliferation potential through their endogenous telomerase activity, maintenance of telomere length, and a bypass of replicative senescence in vitro. Differentiation of PSCs results in silencing of the TERT gene and an overall reversion to a mortal, somatic cell phenotype. The precise mechanisms for this controlled transcriptional silencing are complex. Promoter methylation has been suggested to be associated with epigenetic control of telomerase regulation which presents an important prospect for understanding cancer and stem cell biology. Control of down-regulation of telomerase during differentiation of PSCs provides a convenient model for the study of its endogenous regulation. Telomerase reactivation has the potential to reverse tissue degeneration, drive repair, and form a component of future tissue engineering strategies. Taken together it becomes clear that PSCs provide a unique system to understand telomerase regulation fully and drive this knowledge forward into aging and therapeutic application.

Sign in / Sign up

Export Citation Format

Share Document