Understanding TERT Promoter Mutations: A Common Path to Immortality

Abstract

Telomerase (TERT) activation is a fundamental step in tumorigenesis. By maintaining telomere length, telomerase relieves a main barrier on cellular lifespan, enabling limitless proliferation driven by oncogenes. The recently discovered, highly recurrent mutations in the promoter of TERT are found in over 50 cancer types, and are the most common mutation in many cancers. Transcriptional activation of TERT, via promoter mutation or other mechanisms, is the rate-limiting step in production of active telomerase. Although TERT is expressed in stem cells, it is naturally silenced upon differentiation. Thus, the presence of TERT promoter mutations may shed light on whether a particular tumor arose from a stem cell or more differentiated cell type. It is becoming clear that TERT mutations occur early during cellular transformation, and activate the TERT promoter by recruiting transcription factors that do not normally regulate TERT gene expression. This review highlights the fundamental and widespread role of TERT promoter mutations in tumorigenesis, including recent progress on their mechanism of transcriptional activation. These somatic promoter mutations, along with germline variation in the TERT locus also appear to have significant value as biomarkers of patient outcome. Understanding the precise molecular mechanism of TERT activation by promoter mutation and germline variation may inspire novel cancer cell-specific targeted therapies for a large number of cancer patients.

Figure 1. Prevalence of TERT promoter mutations in human cancers

The frequency of TERT promoter mutations is plotted for all tumor types in which at least 20 samples have been tested. Horizontal lines indicate Wilson score confidence intervals. In contrast to these tumor types, no TERT promoter mutations were found in the following cancers: oral mucosal melanoma (n=39 (106)), pilocytic astrocytoma (n=111 (107)), medullary thyroid carcinoma (n=24 (34), n=28 (44), n=37 (67)), metastatic bladder adenocarcinoma (n=30 (108)), colorectal adenocarcinoma (n=22 (34)), gastric cancer (n=74 (109)), breast carcinoma (n=88 (34)), cholangiosarcoma (n=28, (34)), dedifferentiated liposarcoma (n=61 (110)), leiomyosarcoma (n=27 (110)), undifferentiated pleomorphic sarcoma (n=40 (110)), myeloid leukemia (n=48 (34)), pancreatic cancer (n=46 (109)), pancreatic acinar carcinoma (n=25 (34)), pancreatic ductal adenocarcinoma (n=24 (34)), prostate carcinoma (n=34 (34)), endometrioid carcinoma (n=43 (111)), leiomyosarcoma (n=22 (111)), endocervical adenocarcinoma (n=25 (111)), endometrial cancer (n=24 (111)), intrahepatic cholangiocarcinoma (n=52 (37)), thymoma (n=47 (109)), head and neck paraganglioma (n=37 (112)), lung squamous cell carcinoma (n=25 (78)).

Figure 2. Percentage of C228T mutations within tumor types harboring high TERT promoter mutation frequency

Each oval indicates the percentage of C228T mutations observed within TERT mutant tumors (aggregated across studies) for a specific cancer type. A value of 50% means there is equal occurrence of C228T and C250T within that cancer type. Only studies with 20 or more samples and only cancer types with 20 or more observed mutations were included. The cancers types were grouped as in figure 1.

Figure 3. GABPA and MAX binding at the TERT promoter in ENCODE cell lines

ChIP-seq coverage for GABPA and MAX is displayed at the TERT promoter for MCF-7 (WT), HepG2 (C228T), and SK-N-SH (C228T) cells respectively. MAX binding is observed in all three cell lines while GABPA binding is specifically associated with TERT promoter mutation status.

Figure 4. A model for the activation of the mutant TERT promoter by GABP recruitment as a heterotetramer

The GABP heterotetramer is made up of two GABPA(green) and two GABPB(blue) subunits. GABPA is responsible for direct DNA binding, and one subunit is hypothesized to bind to the promoter mutation (stars in blue sections) while the other binds to a native ETS binding site further downstream (red highlighted section).