The reactivation of telomerase is a key mechanism in the unrestricted growth of cancer cells. Malignant pleural mesothelioma (MPM) is a form of cancer originating from the mesothelium, a cell layer covering the lungs and the inside of the chest wall.
Telomerase is activated in mesothelioma owing to excess production of TERT - its main component. Until now, the mechanisms underlying the reactivation of the responsible TERT gene were largely unclear.
Researchers at MedUni Vienna have now shown that a subgroup of MPM with an especially aggressive and genetically distinct form of the disease harbours an activating point mutation in the promoter of the TERT gene.
The promoter region of a gene controls its activity but does not code for the protein itself. The research article, published in the prestigious American journal Clinical Cancer Research, provides important prognostic information but also develops new targeted treatment strategies for MPM patients.
The publication is the result of a translational collaboration between MedUni Vienna's Division of Cancer Research, the Division of Cardiac Surgery at MedUni Vienna and Vienna General Hospital, and the Comprehensive Cancer Center (CCC), a joint institution of the two organisations.
Non-coding mutations driving cancer
Typical genomic changes in cancer cells are in most cases coding, meaning that they lead to the production of modified proteins, but comparably less is known about the central significance of mutations in the regulatory regions.
These regulate the gene expression, i.e. if and when genes are read (transcribed) and consequently the amount of the respective protein produced. The most important regulatory regions of genes are termed promoters. In 2013, activating point mutations in the region of the TERT gene promoters were discovered in a family with an extremely high incidence of cancer.
These mutations represent one of the most common genomic changes in some types of tumours, such as glioblastoma and melanoma. Regarding MPM, the study by the CCC has now shown that, despite a general activation of telomerase in this form of cancer, the TERT promoter is only mutated in a relatively small subgroup of patients.
These MPM tumours are particularly aggressive and are characterised by a specific genetic profile. This observation in patient populations in various European countries suggests that TERT promoter mutations not only facilitate the activation of telomerase, but are also associated with a specific sequence of malignant transformation.
Cell model experiments
Led by Walter Berger, the team of researchers carrying out the study produced immortalised cell models using a variety of surgical specimens from MPM patients. The models enabled them to investigate factors relating to aggressivity as well as response to innovative drugs. Inhibition of a specific protein involved in the activation of the mutated TERT promoter appears to be here a particularly promising approach.
The mutation in the TERT promoter leads to increased binding of transcription factors, called ETS factors, which then directly activate the TERT gene."
Walter Berger, Member, Comprehensive Cancer Center, Institute of Cancer Research, Medical University of Vienna
We are currently investigating whether a pharmacological blockade of the ETS factors has potential as a new treatment option for patients with TERT promoter-mutated MPM. If this proves to be the case, the mutation would be both a biomarker for the selection of suitable patients and a therapeutic target - an ideal combination for precision medicine."
MPM: asbestos-related cancer with poor prognosis
MPM is common in occupation groups at risk from asbestos exposure, and is especially resistant to treatment. Asbestos is largely banned in Central Europe, although it continues to be used unchecked in newly industrialised countries.
As onset of the disease can happen 20 years or more after exposure, cases of MPM are also still increasing in the EU. Fresh insights into the mechanisms of malignant transformation to facilitate the development of new targeted therapies are therefore urgently required.
Pirker, C., et al. (2020) Telomerase reverse transcriptase promoter mutations identify a genomically defined and highly aggressive human pleural mesothelioma subgroup. Clinical Cancer Research. doi.org/10.1158/1078-0432.CCR-19-3573.