Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism

Abstract

TERT promoter mutations (TPMs) are the most common non-coding mutations in cancer. The timing and consequences of TPMs have not been fully established. Here we show that TPMs acquired at the transition from benign nevus to malignant melanoma do not support telomere maintenance. In vitro experiments revealed that TPMs do not prevent telomere attrition, resulting in cells with critically short and unprotected telomeres. Immortalization by TPMs requires a gradual upregulation of telomerase, coinciding with telomere fusions. These data suggest that TPMs contribute to tumorigenesis by promoting immortalization and genomic instability in two phases. In an initial phase, TPMs do not prevent bulk telomere shortening but extend cellular life-span by healing the shortest telomeres. In the second phase, the critically short telomeres lead to genome instability and telomerase is further upregulated to sustain cell proliferation.

The TERT promoter mutation status and MGMT promoter methylation status, combined with dichotomized MRI‐derived and clinical features, predict adult primary glioblastoma survival

“…Our study showed that TERT promoter mutations (66.42%) occur in many primary GBMs, and the frequency at which these were detected was in line with previous studies (58%‐75%) 21, 22. TERT promoter mutations are frequency associated with malignant tumor progression and a capacity for enhanced cell proliferation 23. The unenhanced region on MRI, which represents pathological necrosis, reflects tumor progression.…”

Combined genetic and epigenetic alterations of the TERT promoter affect clinical and biological behavior of bladder cancer

“…Importantly, TERT promoter mutations are associated with worse clinical outcome in most studies further highlighting the role of telomerase activation in tumor progression and recurrence . Noteworthy, not all TERTp Mut tumors display telomerase activation and non‐ TERTp Mut UBC may express TERT suggesting that the presence of additional mechanisms are necessary for telomerase activation in UBC …”

TERTgene: its function and dysregulation in cancer

“…Comparison between matched naevi and adjacent melanoma demonstrates increased TERT expression in the malignant component with a TERT promoter mutation 49. A recent study by Chiba et al 50 demonstrated that, by contrast, telomere length was shorter in the melanomas than in the adjacent naevi 50. In this latter study, the investigators propose that TERT promoter mutations act in two stages, with the first phase having moderately increased TERT expression yet at a level insufficient to prevent telomere shortening, resulting in shorter telomeres and delayed replicative senescence.…”