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Expression level of hTERT is regulated by somatic mutation and common single nucleotide polymorphism at promoter region in glioblastoma.

ABSTRACT: We investigated the role of somatic mutations and a common single nucleotide polymorphism (SNP) in the hTERT promoter region on hTERT expression and clinical outcomes. The hTERT promoter region was sequenced from 48 glioblastomas. hTERT expression was analyzed by quantitative real time-PCR. The association between hTERT promoter genetic changes and other genomic events and clinical variables common in gliomas were examined. C228T and C250T somatic mutations were found in 60.4% of glioblastomas, and a common SNP (T349C) was found in 66.6%. Somatic mutations and the SNP likely have opposing effects on hTERT expression. hTERT expression was significantly higher in the C228T or C250T mutated tumors. Tumors with the T349C genotype showed lower hTERT expression when C228T or C250T mutations were present. However, no significant survival differences were observed among the groups with or without hTERT promoter mutations and SNP. There was a significant association between genetic changes in the hTERT promoter and patient age as well as MGMT promoter methylation and EGFR amplification. hTERT expression is modulated by somatic mutations in the hTERT promoter as well as a common polymorphism. However, hTERT related genomic changes have limited value as an independent prognostic factor for clinical outcomes in glioblastomas.

SUBMITTER: Park CK

PROVIDER: S-EPMC4102818 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Expression level of hTERT is regulated by somatic mutation and common single nucleotide polymorphism at promoter region in glioblastoma.

Park Chul-Kee CK Lee Se-Hoon SH Kim Ji Young JY Kim Ja Eun JE Kim Tae Min TM Lee Soon-Tae ST Choi Seung Hong SH Park Sung-Hye SH Kim Il Han IH

Oncotarget 20140501 10

We investigated the role of somatic mutations and a common single nucleotide polymorphism (SNP) in the hTERT promoter region on hTERT expression and clinical outcomes. The hTERT promoter region was sequenced from 48 glioblastomas. hTERT expression was analyzed by quantitative real time-PCR. The association between hTERT promoter genetic changes and other genomic events and clinical variables common in gliomas were examined. C228T and C250T somatic mutations were found in 60.4% of glioblastomas, ...[more]

PMID: 24930669

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Project description:BACKGROUND:The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. METHODS:Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue. RESULTS:Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P=1.2×10(-15); allelic association with idiopathic pulmonary fibrosis, P=2.5×10(-37)). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. CONCLUSIONS:A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.).

Project description:The catalytic activity of human Telomerase Reverse Transcriptase (TERT) compensates for the loss of telomere length, eroded during each cell cycle, to ensure a correct division of stem and germinal cells. In human tumors, ectopic TERT reactivation, most frequently due to hotspot mutations in the promoter region (TERTp), i.e. c.1-124 C?>?T, c.1-146 C?>?T, confers a proliferative advantage to neoplastic cells. In gliomas, TERTp mutations (TERTpmut) mainly occur in oligodendroglioma and glioblastoma. We screened, for TERTp hotspot mutations, 301 adult patients with gliomas and identified heterozygous mutations in 239 cases: 94% of oligodendroglioma, 85% of glioblastoma, and 37.5% of diffuse/anaplastic astrocytoma. Besides the recurrent c.1-124 C?>?T and c.1-146 C?>?T, two cases of glioblastoma harbored novel somatic TERTp variants, which consisted of a tandem duplications of 22 nucleotides, i.e. a TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, both located downstream c.1-124 C?>?T and c.1-146 C?>?T. In silico analysis predicted the formation of 119 and 108 new transcription factor's recognition sites for TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, respectively. TERTp duplications (TERTpdup) mainly affected the binding capacity of two transcription factors' families, i.e. the members of the E-twenty-six and the Specificity Protein/Krüppel-Like Factor groups. In fact, these new TERTpdup significantly enhanced the E-twenty-six transcription factors' binding capacity, which is also typically increased by the two c.1-124 C?>?T/c.1-146 C?>?T hotspot TERTpmut. On the other hand, they were distinguished by enhanced affinity for the Krüppel proteins. The luciferase assay confirmed that TERTpdup behaved as gain-of-function mutations causing a 2,3-2,5 fold increase of TERT transcription. The present study provides new insights into TERTp mutational spectrum occurring in central nervous system tumors, with the identification of new recurrent somatic gain-of-function mutations, occurring in 0.8% of glioblastoma IDH-wildtype.

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Expression level of hTERT is regulated by somatic mutation and common single nucleotide polymorphism at promoter region in glioblastoma.

Publications

Expression level of hTERT is regulated by somatic mutation and common single nucleotide polymorphism at promoter region in glioblastoma.

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