TERT promoter mutations in cancer

One of the hallmarks of carcinogenesis is immortalization of cancer cells achieved by reactivation of telomerase. The function of this enzyme is to add a long stretch of TTAGGG repeats to the ends of each chromosome to protect the genetic material. Normally telomerase is expressed in stem cells during development and silenced in somatic cells at the time of differentiation. In cancer cells telomerase prevents telomere shortening and leads to unlimited cellular proliferation, vital for subsequent transformation. Almost 90 % of human cancers shows reactivation of telomerase. The enzyme is built mainly by two components, telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC).

TERT promoter mutations illustration

One of the most pivotal mechanisms leading to telomerase activation are somatic mutation within TERT promoter, first described by the previous laboratory of the current Pilsen ERA Chair (Horn et al 2013 Science). Two somatic mutations (C>T transitions) located 124 and 146 bp upstream of the translation initiation has been reported in various cancer types including melanomas, glioblastomas, and bladder, thyroid and hepatocellular carcinoma, in most of these as the most common somatic mutation. Both of them are responsible overexpression of TERT through creation of a de novo binding site for ETS family of transcription factors. Additionally coexistence of polymorphism rs2853669 (located within pre-existing Ets2 biding site of the TERT promoter) with TERT mutations can serve as clinical biomarker predicting patients overall survival. The Laboratory of Translational Cancer Genomics together with Laboratory of Pharmacogenomics are presently working on TERT promoter mutation profiling in hepatocellular carcinoma and adjacent non tumour tissue.