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.
Highlights
Recent advances in studies regarding non-coding mutations in cancer have inaugurated new chapters for oncogenesis
We identified a common single nucleotide polymorphism (SNP) of T349C in the human telomerase reverse transcriptase (hTERT) promoter region in both tumor and blood samples from 32 patients (66.6%)
In 85-90% of human cancers, this occurs through upregulation of telomerase activity, while in 10-15% of cancers, it occurs through alternative lengthening of telomeres.[14]
Summary
Recent advances in studies regarding non-coding mutations in cancer have inaugurated new chapters for oncogenesis. In the hTERT promoter region, there is a single nucleotide polymorphism (SNP), chr5:1,295,349 T>C (rs2853669, T349C), that has been shown to affect telomerase activity and telomere length.[7,8,9] This functional T349C SNP interferes with Ets transcription factor binding and lowers hTERT expression in both T/C heterozygotes and C/C homozygotes.[8] A recent study reported that the T349C SNP may even affect the clinical outcome of bladder cancer patients when paired with somatic mutations of C228T or C250T.[10] This common SNP has been associated with breast cancer risk; these reports are controversial.[11,12,13]
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