Association between functional TERT promoter polymorphism rs2853669 and cervical cancer risk in South Indian women

Vinothkumar, Vilvanathan; Arun, Kanagaraj; Arunkumar, Ganesan; Revathidevi, Sundaramoorthy; Ramani, Rajendren; Bhaskar, L. V. K. S.; Murugan, Avaniyapuram Kannan; Munirajan, Arasambattu Kannan

doi:10.3892/mco.2020.2003

Cited by 9 publications

(10 citation statements)

References 56 publications

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“…A previous study found TERT T349C to be present in 52% of melanoma cell lines ( 43 ). The high frequency of T349C also aligns with previous studies on other cancers ( 70 – 72 ). All the TERT promoter mutations C228T and C250T and 14/17 (82%) BRAF/NRAS mutations co-occurred with the germline TERT promoter variant T349C ( Figure 2 ).…”

Section: Resultssupporting

confidence: 90%

“…This TERT SNP has been identified in a range of other cancers and may act to disrupt a pre-existing ETS binding site in the TERT promoter ( 81 ). Nevertheless, its prognostic role remains controversial with contrasting reports on its influence on TERT expression and differing conclusions on its prognostic value ( 43 , 70 – 72 , 82 , 83 , 85 – 88 ). In melanoma, TERT T349C has been reported to modify the effects of somatic TERT promoter mutations leading to increased survival in melanoma ( 40 ) and this may be mediated through a lengthening of telomeres ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

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Anchored Multiplex PCR Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA

et al. 2022

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Detection of melanoma mutations using circulating tumor DNA (ctDNA) is a potential alternative to using genomic DNA from invasive tissue biopsies. To date, mutations in the GC-rich TERT promoter region, which is commonly mutated in melanoma, have been technically difficult to detect in ctDNA using next-generation sequencing (NGS) panels. In this study, we developed a custom melanoma NGS panel for detection of ctDNA, which encompasses the top 15 gene mutations in melanoma including the TERT promoter. We analyzed 21 stage III and IV melanoma patient samples who were treatment-naïve or on therapy. The overall detection rate of the custom panel, based on BRAF/NRAS/TERT promoter mutations, was 14/21 (67%) patient samples which included a TERT C250T mutation in one BRAF and NRAS mutation negative sample. A BRAF or NRAS mutation was detected in the ctDNA of 13/21 (62%) patients while TERT promoter mutations were detected in 10/21 (48%) patients. Co-occurrence of TERT promoter mutations with BRAF or NRAS mutations was found in 9/10 (90%) patients. The custom ctDNA panel showed a concordance of 16/21 (76%) with tissue based-detection and included 12 BRAF/NRAS mutation positive and 4 BRAF/NRAS mutation negative patients. The ctDNA mutation detection rate for stage IV was 12/16 (75%) and for stage III was 1/5 (20%). Based on BRAF, NRAS and TERT promoter mutations, the custom melanoma panel displayed a limit of detection of ~0.2% mutant allele frequency and showed significant correlation with droplet digital PCR. For one patient, a novel MAP2K1 H119Y mutation was detected in an NRAS/BRAF/TERT promoter mutation negative background. To increase the detection rate to >90% for stage IV melanoma patients, we plan to expand our custom panel to 50 genes. This study represents one of the first to successfully detect TERT promoter mutations in ctDNA from cutaneous melanoma patients using a targeted NGS panel.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Anchored Multiplex PCR Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA

et al. 2022

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“…It obstructs an ETS2 binding site, located close to an E-box. Previous studies showed that TERTp mutations creating a putative binding site for ETS, resulted in TERT upregulation and increased telomerase activity, while mutations at the ETS2 binding site suppressed c-MYC binding to the E-box ( 146 , 147 ). Studies on rs2853669 showed that it is significantly associated with poor survival and increased cancer risk rate in hepatocellular carcinoma patients ( 146 ).…”

Section: Tert Gene Polymorphismsmentioning

confidence: 99%

“…Previous studies showed that TERTp mutations creating a putative binding site for ETS, resulted in TERT upregulation and increased telomerase activity, while mutations at the ETS2 binding site suppressed c-MYC binding to the E-box ( 146 , 147 ). Studies on rs2853669 showed that it is significantly associated with poor survival and increased cancer risk rate in hepatocellular carcinoma patients ( 146 ). In contrast, it was also observed to correlate with improved survival in patients with clear cell renal cell carcinoma, melanoma and glioblastoma ( 148 ).…”

Section: Tert Gene Polymorphismsmentioning

confidence: 99%

TERT—Regulation and Roles in Cancer Formation

et al. 2020

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Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase. Telomerase complex plays a key role in cancer formation by telomere dependent or independent mechanisms. Telomere maintenance mechanisms include complex TERT changes such as gene amplifications, TERT structural variants, TERT promoter germline and somatic mutations, TERT epigenetic changes, and alternative lengthening of telomere. All of them are cancer specific at tissue histotype and at single cell level. TERT expression is regulated in tumors via multiple genetic and epigenetic alterations which affect telomerase activity. Telomerase activity via TERT expression has an impact on telomere length and can be a useful marker in diagnosis and prognosis of various cancers and a new therapy approach. In this review we want to highlight the main roles of TERT in different mechanisms of cancer development and regulation.

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“…Nevertheless, alterations in regulatory regions are associated with many complex traits (Deplancke et al, 2016). Particularly, there are recurrent functional mutations in regulatory regions (Saini and Gordenin, 2018), such as the well-studied recurrent C>T transition that creates a strong binding site for the GABP transcription factor in the TERT promoter and is associated with increased cancer risk (Bell et al, 2015;Horn et al, 2013;Vinothkumar et al, 2020). Somatic mutations are caused by a combination of DNA damage and DNA repair failures (Volkova et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Enhanced C/EBPs binding to C>T mismatches facilitates fixation of CpG mutations

Ershova

Eliseeva

Nikonov

et al. 2020

Preprint

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Knowledge of mechanisms responsible for mutagenesis of adult stem cells is crucial to track genomic alterations that may affect cell renovation and provoke malignant cell transformation. Mutations in regulatory regions are widely studied nowadays, though mostly in cancer. In this study, we decomposed the mutation signature of adult stem cells, mapped the corresponding mutations into transcription factor binding regions, and assessed mutation frequency in sequence motif occurrences. We found binding sites of C/EBP transcription factors strongly enriched with [C>T]G mutations within the core CG dinucleotide related to deamination of the methylated cytosine. This effect was also exhibited in related cancer samples. Structural modeling predicted enhanced CEBPB binding to the consensus sequence with the [C>T]G mismatch, which was then confirmed in the direct experiment. We propose that it is the enhanced binding of C/EBPs that shields C>T transitions from DNA repair and leads to selective accumulation of the [C>T]G mutations within binding sites.

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Association between functional TERT promoter polymorphism rs2853669 and cervical cancer risk in South Indian women

Cited by 9 publications

References 56 publications

Anchored Multiplex PCR Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA

Anchored Multiplex PCR Custom Melanoma Next Generation Sequencing Panel for Analysis of Circulating Tumor DNA

TERT—Regulation and Roles in Cancer Formation

Enhanced C/EBPs binding to C>T mismatches facilitates fixation of CpG mutations

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