DNA carries the instructions for all cellular processes within its genes. Mutations, or changes in this blueprint, can alter how genes function. One such gene, TERT (Telomerase Reverse Transcriptase), helps maintain telomeres, the protective caps at the ends of our chromosomes that prevent damage during cell division. The TERT gene provides instructions for a component of the telomerase enzyme, which adds DNA segments to telomeres, preserving their length.
Genetic Basis of TERT Promoter Mutations
A gene’s promoter region acts like a switch, controlling when and how much of its instructions are read and converted into proteins. The TERT gene’s promoter regulates TERT protein production. In most mature human cells, the TERT gene is largely inactive, resulting in very low telomerase activity. This leads to a natural shortening of telomeres with each cell division, a process linked to cellular aging.
However, specific mutations within the TERT promoter region can disrupt this normal regulation. The most common TERT promoter mutations are single nucleotide changes, specifically C228T and C250T. These occur at positions -124 and -146 base pairs upstream from the gene’s translational start site, respectively.
These mutations create new binding sites for ETS transcription factors. When these factors bind, they act as activators, significantly increasing TERT promoter activity. This leads to a substantial increase in TERT protein production and, consequently, telomerase enzyme activity. As a result, cells can maintain their telomere length more effectively.
Impact on Cellular Processes and Disease
Increased telomerase activity from TERT promoter mutations has significant consequences for cellular processes, particularly in disease. In normal cells, telomere shortening acts as a natural barrier to uncontrolled cell division, eventually leading to cellular senescence or programmed cell death. However, elevated telomerase activity bypasses this limit. By continuously maintaining telomere length, cells with TERT promoter mutations can divide indefinitely, a characteristic feature of cancer cells.
This ability to achieve “immortality” is a fundamental step in the development and progression of many cancers. TERT promoter mutations are among the most common genetic alterations found in human cancers, identified in over 50 distinct cancer types. In some cancers, these mutations are considered early genetic events in tumor formation.
These mutations are frequently observed in specific cancer types. They are found in up to 71% of melanoma cases and 66% of bladder cancers. Glioblastoma, an aggressive brain tumor, also commonly harbors TERT promoter mutations, with a prevalence of up to 83%. Thyroid cancers, particularly advanced forms, also show a high frequency of these mutations.
Identifying TERT Promoter Mutations and Their Clinical Relevance
Detecting TERT promoter mutations is important in clinical settings due to their role as biomarkers. Various methods identify these genetic changes. Genetic sequencing, such as Sanger sequencing and Next-Generation Sequencing (NGS), precisely identifies the C228T and C250T mutations within the TERT promoter region. Polymerase Chain Reaction (PCR)-based assays, including real-time PCR and droplet digital PCR (ddPCR), also provide sensitive and specific detection.
Identifying TERT promoter mutations holds significant clinical relevance for diagnosis, prognosis, and guiding treatment decisions. As a diagnostic biomarker, their presence can help classify certain tumor types. For example, in gliomas, TERT promoter mutations are a key molecular diagnostic marker, aiding in central nervous system tumor classification. They also serve as prognostic indicators, predicting disease aggressiveness or patient outcome. In many cancers, including melanoma, thyroid cancer, and gliomas, these mutations are associated with decreased overall survival.
TERT promoter mutations can influence therapeutic strategies. In certain cancers, their presence might indicate a patient’s potential response to specific treatments or eligibility for clinical trials. For instance, in hepatocellular carcinoma, TERT promoter mutations are linked to reduced survival and may represent a distinct subgroup of liver cancers. Understanding the TERT promoter’s mutational status helps oncologists tailor more personalized and effective treatment plans for patients.