TERT promoter status and gene copy number gains: effect on TERT expression and association with prognosis in breast cancer.

Mathilde Gay-Bellile,Maud Privat,Frédérique Penault-Llorca,Lauren Véronèse,Philippe Vago,Fabrice Kwiatkowski,Yves-Jean Bignon,Catherine Abrial,Eleonore Eymard-Pierre,Patricia Combes,Marie-Mélanie Dauplat,Andrei Tchirkov,Anne Cayre,Marie-Ange Mouret-Reynier

doi:10.18632/oncotarget.20560

Abstract

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

Highlights

The telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase that maintains telomere length
The T349C single nucleotide polymorphisms (SNP) was identified in 42.3% of tumor biopsies and 48.9% of residual tumors (Table 1)
We found that TERT gains were relatively frequent events in both cohorts

Summary

Introduction

The telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase that maintains telomere length. Telomerase activity occurs in more than 90% of cancers [1]. One of the hallmark features of tumor cells, it contributes to their growth advantage and survival, and upregulation of the TERT gene is the major mechanism of telomerase activation in human cancer [2]. European population with tumor aggressiveness [3] and poor survival after adjuvant [4] and neoadjuvant [5] chemotherapy. Several molecular events can modify TERT expression in cancer cells. Somatic mutations and functional single nucleotide polymorphisms (SNP) in the TERT promoter can lead to changes in the expression of the gene [6]. Overexpression of the oncogene MYC can directly enhance TERT expression by increased binding to the TERT promoter [7]. Increased copy number or amplification of the TERT gene can result in TERT upregulation [8,9,10]

Methods

Results

Conclusion