<i>TERT</i> promoter status and gene copy number gains: effect on <i>TERT</i> expression and association with prognosis in breast cancer

Abstract

Upregulation of the telomerase reverse transcriptase (<i>TERT</i>) gene in human cancers leads to telomerase activation, which contributes to the growth advantage and survival of tumor cells. Molecular mechanisms of <i>TERT</i> upregulation are complex, tumor-specific and can be clinically relevant. To investigate these mechanisms in breast cancer, we sequenced the <i>TERT</i> promoter, evaluated <i>TERT</i> copy number changes and assessed the expression of the <i>MYC</i> oncogene, a known transcriptional <i>TERT</i> regulator, in two breast cancer cohorts comprising a total of 122 patients. No activating <i>TERT</i> promoter mutations were found, suggesting that this mutational mechanism is not likely to be involved in <i>TERT</i> upregulation in breast cancer. The T349C promoter polymorphism found in up to 50% of cases was not correlated with <i>TERT</i> expression, but T349C carriers had significantly shorter disease-free survival. <i>TERT</i> gains (15-25% of cases) were strongly correlated with increased <i>TERT</i> mRNA expression and worse patient prognosis in terms of disease-free and overall survival. Particularly aggressive breast cancers were characterized by an association of <i>TERT</i> gains with <i>MYC</i> overexpression. These results evidence a significant effect of gene copy number gain on the level of <i>TERT</i> expression and provide a new insight into the clinical significance of <i>TERT</i> and <i>MYC</i> upregulation in breast cancer.