A Pan-Cancer Study of Somatic TERT Promoter Mutations and Amplification in 30,773 Tumors Profiled by Clinical Genomic Sequencing

Gupta, Sounak; Vanderbilt, Chad; Lin, David M.; Benhamida, Jamal; Jungbluth, Achim A.; Rana, Satshil; Boroujeni, Amir Momeni; Chang, Jason C.; Mcfarlane, Tiffany; Salazar, Paulo; Mullaney, Kerry; Middha, Sumit; Zehir, Ahmet; Gopalan, Anuradha; Bale, Tejus; Ganly, Ian; Arcila, Maria E.; Benayed, Ryma; Berger, Michael F.; Ladanyi, Marc; Doğan, Snjezana

doi:10.1016/j.jmoldx.2020.11.003

Cited by 26 publications

(30 citation statements)

References 54 publications

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“…Our results are in consonance with previous studies: TERT expression is commonly mediated by genetic and epigenetic mechanisms [ 3 , 14 , 15 , 57 , 58 ] and only detectable in metastatic PPGL but not in non-metastatic cases [ 59 ]. In addition, among all the mechanisms associated with TERT expression, we found that copy number gains of TERT locus showed the highest levels of TERT transcriptional activation [ 14 , 15 , 60 , 61 ]. Similarly, rearrangements in the TERT promoter have been reported to be associated with high levels of TERT expression [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, among all the mechanisms associated with TERT expression, we found that copy number gains of TERT locus showed the highest levels of TERT transcriptional activation [ 14 , 15 , 60 , 61 ]. Similarly, rearrangements in the TERT promoter have been reported to be associated with high levels of TERT expression [ 60 ]. This mechanism could explain the data observed in three TERT -WT samples of our series, which showed equally high levels as samples with TERT locus gains.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma

Monteagudo

Martínez

Leandro‐García

et al. 2021

Cancers

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One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma

Monteagudo

Martínez

Leandro‐García

et al. 2021

Cancers

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“…Specifics regarding the MSK-IMPACT assay have been previously reported [5,19,20]. This assay involves hybridization capture-based library preparation followed by deep sequencing of select noncoding regions and 6614 proteincoding exons of 468 genes (previous versions interrogated 341 and 410 genes) including TERT [6]. Sequencing 500 bases upstream of the TERT promoter allows for the identification of "hotspot" promoter mutations as well as structural variants that may occur in this region [6].…”

Section: Next Generation Sequencing-based Molecular Profilingmentioning

confidence: 99%

“…This assay involves hybridization capture-based library preparation followed by deep sequencing of select noncoding regions and 6614 proteincoding exons of 468 genes (previous versions interrogated 341 and 410 genes) including TERT [6]. Sequencing 500 bases upstream of the TERT promoter allows for the identification of "hotspot" promoter mutations as well as structural variants that may occur in this region [6]. In addition, the homogenous distribution of single nucleotide polymorphism tiling probes across the genome allows for assessment of copy number alterations.…”

Section: Next Generation Sequencing-based Molecular Profilingmentioning

confidence: 99%

“…This prevents the initiation of repair pathways and allows neoplastic cells to escape telomere crisis [1]. Alterations of the TERT gene such as "hotspot" promoter mutations, amplifications and promoter rearrangements have been associated with increased TERT expression and these alterations have been frequently seen in multiple cancer types [2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Molecular 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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COL1A1::PDGFB fusion uterine sarcoma with a TERT promoter mutation

Lu,

Chen,

Zeng

et al. 2023

Genes Chromosomes & Cancer

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COL1A1::PDGFB fusion uterine sarcoma is a rare uterine mesenchymal tumor with some clinicopathological features that overlap with those of soft tissue dermatofibrosarcoma protuberans. However, the varied clinicopathologic and genetic characteristics have not been fully revealed, which may be a potential pitfall for diagnosis. Here, we present a case of COL1A1::PDGFB fusion‐positive uterine sarcoma in a 49‐years‐old female. Histologically, the tumor from the initial marginal excision predominantly exhibited high‐grade fibrosarcomatous and myxofibrosarcoma‐like appearances, while a low‐grade focal area displaying storiform growth was identified in the residual tumor after subsequently extended resection. Immunohistochemically, the high‐grade components mainly exhibited focal positivity for CD34 and mutated‐type p53 immunoreactivity, whereas the low‐grade component showed diffuse positivity for CD34 and wild‐type p53 staining. The COL1A1::PDGFB fusion was confirmed by fluorescence in situ hybridization and next‐generation sequencing. In addition, the TERT‐124 C > T mutation was further identified in this lesion's fibrosarcomatous and classic storiform components. To the best of our knowledge, this is the first described case of COL1A1::PDGFB fusion uterine sarcoma with a TERT promoter mutation, which might be a novel genetic finding associated with tumorigenesis of this rare tumor.

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A Pan-Cancer Study of Somatic TERT Promoter Mutations and Amplification in 30,773 Tumors Profiled by Clinical Genomic Sequencing

Cited by 26 publications

References 54 publications

Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma

Analysis of Telomere Maintenance Related Genes Reveals NOP10 as a New Metastatic-Risk Marker in Pheochromocytoma/Paraganglioma

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

COL1A1::PDGFB fusion uterine sarcoma with a TERT promoter mutation

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