Abstract:BackgroundThe hTERT (human telomerase reverse transcriptase) gene contains five variable number tandem repeats (VNTR) and previous studies have described polymorphisms for hTERT-VNTR2-2nd. We investigated how allelic variation in hTERT-VNTR2-2nd may affect susceptibility to prostate cancer.MethodsA case-control study was performed using DNA from 421 cancer-free male controls and 329 patients with prostate cancer. In addition, to determine whether the VNTR polymorphisms have a functional consequence, we examine… Show more
“…Moreover, there are also several reports indicating that minisatellite polymorphisms can influence gene expression. 16 , 17 , 24 , 25 , 26 , 27 , 28 …”
Section: Discussionmentioning
confidence: 99%
“…Similar results for transcriptional regulation by minisatellite fragments were previously reported with H-Ras , IL-1α, IGF2 , MUC6 and TERT genes. 16 , 17 , 24 , 25 , 26 Minisatellites of IL-1α, MUC6 and TERT may control gene expression in cancer cell lines, although these are located in the intronic regions of genes. 16 , 17 We suggest that BORIS –MS2, located in the promoter region, differentially regulates the gene transcription in cancer cells and normal cells.…”
Section: Discussionmentioning
confidence: 99%
“…In addition, it is the fourth most common cancer in females worldwide, based on GLOBOCAN 2008 estimates, 15 and it is a major public health problem in Korea. Because some minisatellite alleles are associated with human diseases, 16 , 17 we investigated the relationship between cancer predisposition and minisatellite variants in BORIS 6 , 12 and revealed increased susceptibility in young patients with breast cancer containing short rare minisatellite alleles of BORIS -MS2. To determine whether allelic variation in BORIS minisatellites influences susceptibility to lung cancer, a case–control study was performed using a PCR-based method.…”
Aberrant expression of BORIS/CTCFL (Brother of the Regulator of Imprinted Sites/CTCF-like protein) is reported in different malignancies. In this study, we characterized the entire promoter region of BORIS/CTCFL, including the CpG islands, to assess the relationship between BORIS expression and lung cancer. To simplify the construction of luciferase reporter cassettes with various-sized portions of the upstream region, genomic copies of BORIS were isolated using TAR cloning technology. We analyzed three promoter blocks: the GATA/CCAAT box, the CpG islands and the minisatellite region BORIS-MS2. Polymorphic minisatellite sequences were isolated from genomic DNA prepared from the blood of controls and cases. Of the three promoter blocks, the GATA/CCAAT box was determined to be a critical element of the core promoter, while the CpG islands and the BORIS-MS2 minisatellite region were found to act as regulators. Interestingly, the polymorphic minisatellite region BORIS-MS2 was identified as a negative regulator that repressed the expression levels of luciferase reporter cassettes less effectively in cancer cells compared with normal cells. We also examined the association between the size of BORIS-MS2 and lung cancer in a case–control study with 590 controls and 206 lung cancer cases. Rare alleles of BORIS-MS2 were associated with a statistically significantly increased risk of lung cancer (odds ratio, 2.04; 95% confidence interval, 1.02–4.08; and P=0.039). To conclude, our data provide information on the organization of the BORIS promoter region and gene regulation in normal and cancer cells. In addition, we propose that specific alleles of the BORIS-MS2 region could be used to identify the risk for lung cancer.
“…Moreover, there are also several reports indicating that minisatellite polymorphisms can influence gene expression. 16 , 17 , 24 , 25 , 26 , 27 , 28 …”
Section: Discussionmentioning
confidence: 99%
“…Similar results for transcriptional regulation by minisatellite fragments were previously reported with H-Ras , IL-1α, IGF2 , MUC6 and TERT genes. 16 , 17 , 24 , 25 , 26 Minisatellites of IL-1α, MUC6 and TERT may control gene expression in cancer cell lines, although these are located in the intronic regions of genes. 16 , 17 We suggest that BORIS –MS2, located in the promoter region, differentially regulates the gene transcription in cancer cells and normal cells.…”
Section: Discussionmentioning
confidence: 99%
“…In addition, it is the fourth most common cancer in females worldwide, based on GLOBOCAN 2008 estimates, 15 and it is a major public health problem in Korea. Because some minisatellite alleles are associated with human diseases, 16 , 17 we investigated the relationship between cancer predisposition and minisatellite variants in BORIS 6 , 12 and revealed increased susceptibility in young patients with breast cancer containing short rare minisatellite alleles of BORIS -MS2. To determine whether allelic variation in BORIS minisatellites influences susceptibility to lung cancer, a case–control study was performed using a PCR-based method.…”
Aberrant expression of BORIS/CTCFL (Brother of the Regulator of Imprinted Sites/CTCF-like protein) is reported in different malignancies. In this study, we characterized the entire promoter region of BORIS/CTCFL, including the CpG islands, to assess the relationship between BORIS expression and lung cancer. To simplify the construction of luciferase reporter cassettes with various-sized portions of the upstream region, genomic copies of BORIS were isolated using TAR cloning technology. We analyzed three promoter blocks: the GATA/CCAAT box, the CpG islands and the minisatellite region BORIS-MS2. Polymorphic minisatellite sequences were isolated from genomic DNA prepared from the blood of controls and cases. Of the three promoter blocks, the GATA/CCAAT box was determined to be a critical element of the core promoter, while the CpG islands and the BORIS-MS2 minisatellite region were found to act as regulators. Interestingly, the polymorphic minisatellite region BORIS-MS2 was identified as a negative regulator that repressed the expression levels of luciferase reporter cassettes less effectively in cancer cells compared with normal cells. We also examined the association between the size of BORIS-MS2 and lung cancer in a case–control study with 590 controls and 206 lung cancer cases. Rare alleles of BORIS-MS2 were associated with a statistically significantly increased risk of lung cancer (odds ratio, 2.04; 95% confidence interval, 1.02–4.08; and P=0.039). To conclude, our data provide information on the organization of the BORIS promoter region and gene regulation in normal and cancer cells. In addition, we propose that specific alleles of the BORIS-MS2 region could be used to identify the risk for lung cancer.
“…These VNTRs were also discussed as having an enhancer function for gene transcription. In vitro studies on PrCa cell lines analyzing the activity of the TERT promoter in combination with different VNTR variants clearly showed an increased luciferase activity for the VNTR2-2nd variants [22,23] . These effects might also be expected for TERT expression and could also increase the individual risk for PrCa.…”
Objective: Recently, recurrent mutations within the core promoter of the human telomerase reverse transcriptase (TERT) gene generating consensus binding sites for ETS transcription factor family members were described in melanomas and other malignancies (e.g. bladder cancer, hepatocellular carcinoma). These mutations were discussed as early drivers for malignant transformation. In prostate cancer (PrCa) TERT expression has been associated with a poor prognosis and higher risk for disease recurrence. The underlying mechanisms for high TERT expression in PrCa have still not been clarified. To date, data on TERT promoter mutation analysis in PrCa are sparse. Therefore, we performed sequence analysis of the core promoter region of the TERT gene in an unselected cohort of prostate tumors. Methods: Sections from 167 formalin-fixed, paraffin-embedded and cryopreserved prostate tumors were microdissected and used for DNA isolation. The mutation hotspot region within the TERT core promoter (-260 to +60) was analyzed by direct Sanger sequencing or SNaPshot analysis. Results: All cases were analyzed successfully. Mutations within the core promoter of the TERT gene were not detected in any of the cases with all tumors exhibiting a wild-type sequence. Conclusion:TERT core promoter mutations reported from several other malignancies were not detected in our unselected cohort of PrCa. These data indicate that alterations within the core promoter of the TERT gene do not play an important role in prostate carcinogenesis.
“…Additional genome‐wide association studies found this region to be associated with increased risk for both pancreatic cancer and lung adenocarcinoma [99–104]. Unlike the studies involving breast cancer, an increased risk of prostate cancer was found to be associated with at least one hTERT variation that influences telomerase expression [105, 106]. Other studies have linked cancer risk and telomerase SNP for several cancers including the following: bladder cancer [106, 107], ovarian cancer [108] and cervix cancer [106].…”
Section: Tert and Terc Variations And Disease Predispositionmentioning
Telomerase is a specialized reverse transcriptase that extends and maintains the terminal ends of chromosomes, or telomeres. Since its discovery in 1985 by Nobel Laureates Elizabeth Blackburn and Carol Greider, thousands of articles have emerged detailing its significance in telomere function and cell survival. This review provides a current assessment on the importance of telomerase regulation and relates it in terms of medical genetics. In this review, we discuss the recent findings on telomerase regulation, focusing on epigenetics and non-coding RNAs regulation of telomerase, such as microRNAs and the recently discovered telomeric-repeat containing RNA transcripts. Human genetic disorders that develop due to mutations in telomerase subunits, the role of single nucleotide polymorphisms in genes encoding telomerase components and diseases as a result of telomerase regulation going awry are also discussed. Continual investigation of the complex regulation of telomerase will further our insight into the use of controlling telomerase activity in medicine.
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