Tert Promoter Mutations Occur Frequently in Gliomas and a Subset of Tumors Derived From Cells With Low Rates of Self-Renewal

Yan, Hai; Killela, Patrick; Reitman, Zachary J.; Jiao, Yuchen; Bettegowda, Chetan; Agrawal, Nishant; Diaz, Laura A.; Friedman, Allan H.; Friedman, Henry S.; Gallia, Gary L.; Giovanella, Beppino C.; Grollman, Arthur P.; He, Tong Chuan; He, Yiping; Hruban, Ralph H.; Jallo, George I.; Mandahl, Nils; Meeker, Alan K.; Mertens, Fredrik; Netto, George; Rasheed, B. Ahmed; Riggins, Gregory J.; Rosenquist, Thomas A.; Schiffman, Mark; Shih, IeM; Theodorescu, Dan; Torbenson, Michael; Velculescu, Victor E.; Wang, T.L.; Wentzensen, Nicolas; Wood, Laura D.; Zhang, M.; Healy, Patrick; Yang, Rui; Diplas, Bill H.; Wang, Z.H.; Greer, Paula K.; Zhu, Huishan; Wang, C.; Carpenter, Austin B.; Herndon, James E.; McLendon, Roger E.; Kinzler, Ken W; Vogelstein, Bert; Papadopoulos, Nick; Bigner, Darrell D.

doi:10.1093/neuonc/nou206.18

Cited by 9 publications

(3 citation statements)

References 44 publications

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“…10 The most prevalent mechanism for telomerase reactivation is TERT promoter mutations which reactivates TERT expression by creating a de novo binding site (TTCCGG) for E26 transformation-specific (ETS) transcription factors, and thereby reactivates telomerase and maintains telomere length in the progression of HCC. 12,13 Although there are two hot spot TERT promoter mutations (G228A at −124 bp and G250A at −146 bp upstream the translation start site) in human cancers, 14,15 G228A occurs dominantly in HCC. 16 Clinically, TERT promoter mutations are related with poor clinical outcomes in multiple types of human cancer, including HCC.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic targeting of PLK1 in TERT promoter‐mutant hepatocellular carcinoma

Tang,

Hu,

Sang

et al. 2024

Clinical & Translational Med

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BackgroundHotspot mutations in the promoter of telomerase reverse transcriptase (TERT) gene are the most common genetic variants in hepatocellular carcinoma (HCC) and associated with poor prognosis of the disease. However, no drug was currently approved for treating TERT promoter mutation positive HCC patients. Here, we aim to explore the potential therapeutic strategy for targeting TERT promoter mutation in HCC.MethodsThe Liver Cancer Model Repository database was used for screening potential drugs to selectively suppress the growth of TERT promoter mutant HCC cells. RNA‐seq, CRISPR‐Cas9 technology and siRNA transfection were performed for mechanistic studies. Cell counting kit‐8 (CCK8) assay and the xenograft tumour models were used for cell growth detection in vitro and in vivo, respectively. Cell apoptosis and cell cycle arrest were analysed by Annexin V‐FITC staining and/or propidium iodide staining.ResultsPLK1 inhibitors were remarkably more sensitive to HCC cells harbouring TERT promoter mutation than wild‐type cells in vitro and in vivo, which were diminished after TERT promoter mutation was edited to the wild‐type nucleotide. Comparing the HCC cells with wild‐type promoter of TERT, PLK1 inhibitors specifically downregulated Smad3 to regulate TERT for inducing apoptosis and G2/M arrest in TERT mutant HCC cells. Moreover, knockout of Smad3 counteracted the effects of PLK1 inhibitors in TERT mutant HCC cells. Finally, a cooperative effect of PLK1 and Smad3 inhibition was observed in TERT mutant cells.ConclusionsPLK1 inhibition selectively suppressed the growth of TERT mutant HCC cells through Smad3, thus contributed to discover a novel therapeutic strategy to treat HCC patients harbouring TERT promoter mutations.Key points TERT promoter mutation confers sensitivity to PLK1 inhibitors in HCC. The selective growth inhibition of TERT mutant HCC cells induced by PLK1 inhibitor was mediated by Smad3. Combined inhibition of PLK1 and Smad3 showed a cooperative anti‐tumor effect in TERT mutant HCC cells.

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Section: Introductionmentioning

confidence: 99%

Therapeutic targeting of PLK1 in TERT promoter‐mutant hepatocellular carcinoma

Tang,

Hu,

Sang

et al. 2024

Clinical & Translational Med

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“…Both give origin to de novo binding sites for transcription factors that belong to the ETS/TCF family and are associated with an increased gene expression from two to four times [17,18]. After they were first described in melanoma, their presence has been identified in several solid tumours, including CNS tumours, and correlated to malignant transformation and unfavourable patient survival [19].…”

Section: Introductionmentioning

confidence: 99%

Human TERT Promoter Mutations in Atypical and Anaplastic Meningiomas

et al. 2021

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Background: The role of telomerase reverse transcriptase (TERT) gene promoter mutations (pTERT) in atypical and anaplastic meningiomas remains controversial. This study aimed to evaluate their impact on the histologic diagnosis and prognosis in a retrospective series of 74 patients with atypical and anaplastic meningioma, including disease progression and relapse. A supplementary panel of 21 benign tumours was used as a control cohort. Materials and Methods: The mutation rate of the pTERT gene was assessed by Sanger sequencing. ATRX protein expression was detected by immunohistochemistry. The phenotypic and genotypic intra-tumour heterogeneity was studied in a sub-group of 12 cases using a Molecular Machines & Industries (MMI) CellCut laser microdissection (LMD) system. Results: pTERT mutations were detected in 12/74 (17.6%) malignant meningiomas. The mutation rate was significantly higher in anaplastic meningiomas (7/23, 30.4%) compared to atypical tumours (5/48, 10.4%) (p = 0.0443). In contrast, the mutation rate was < 5% in benign tumours. All pTERT mutant cases retained nuclear ATRX immunoreactivity. pTERT mutations were significantly associated with the histologic grade (p = 0.0443) and were adverse prognostic factors for anaplastic tumours (p = 0.06). Conclusion: We reported on the pTERT mutation spectrum in malignant meningiomas, supporting their use in the prognostic classification.

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“…Mutations within regulatory elements of enhancers and promoters can be responsible for the development of disorders with the same magnitude as mutations affecting protein-coding genes [10][11][12][13][14]26,27 . A classic example of this is the TERT promoter which is frequently mutated across several cancer types as a mechanism for telomerase reactivation 28 ; it has been observed in 71% of sporadic melanoma and 60-75% of glioblastomas [10][11][12][13][14]26,27 .…”

Section: Introductionmentioning

confidence: 99%

Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

Quevedo

Hawley

et al. 2021

Preprint

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Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and non-coding cancer driver plexuses from somatic mutations. However, differentiating driver and passenger events among non-coding genetic variants remains a challenge to understand the etiology of cancer and inform the delivery of personalized cancer medicine. Herein, we reveal an enrichment of non-coding mutations in cis-regulatory elements that cover a subset of transcription factors linked to tumor progression in luminal breast cancers. Using a cohort of 26 primary luminal ER+PR+ breast tumors, we compiled a catalogue of ~100,000 unique cis-regulatory elements from ATACseq data. Integrating this catalogue with somatic mutations from 350 publicly available breast tumor whole genomes, we identified four recurrently mutated individual cis-regulatory elements. By then partitioning the non-coding genome into cistromes, defined as the sum of binding sites for a transcription factor, we uncovered cancer driver cistromes for ten transcription factors in luminal breast cancer, namely CTCF, ELF1, ESR1, FOSL2, FOXA1, FOXM1 GATA3, JUND, TFAP2A, and TFAP2C in luminal breast cancer. Nine of these ten transcription factors were shown to be essential for growth in breast cancer, with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of non-coding mutations over cis-regulatory elements concatenated into a functional unit drawn from an accessible chromatin catalogue derived from primary cancer tissues.

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Tert Promoter Mutations Occur Frequently in Gliomas and a Subset of Tumors Derived From Cells With Low Rates of Self-Renewal

Cited by 9 publications

References 44 publications

Therapeutic targeting of PLK1 in TERT promoter‐mutant hepatocellular carcinoma

Therapeutic targeting of PLK1 in TERT promoter‐mutant hepatocellular carcinoma

Human TERT Promoter Mutations in Atypical and Anaplastic Meningiomas

Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

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