Presence of TERT Promoter Mutations is a Secondary Event and Associates with Elongated Telomere Length in Myxoid Liposarcomas.

Monica Ventura Ferreira,Till Braunschweig,Anne-Sophie Bouillon,Ruth Knuechel,Tim Brümmendorf,Edgar Jost,Fabian Beier,Martina Crysandt,Barbara Voss

doi:10.3390/ijms19020608

Monica Ventura Ferreira, Till Braunschweig + Show 7 more

Open Access

https://doi.org/10.3390/ijms19020608

Copy DOI

Abstract

The occurrence of TERT promoter mutations has been well described in soft tissue sarcomas (STS). However, the biological role of these mutations as well as their impact on telomere length in STS is still unclear. We analyzed 116 patient samples diagnosed with 22 distinct histological subtypes of bone and STS for the occurrence of TERT promoter mutations by Sanger sequencing. We observed TERT promoter mutations at an overall frequency of 9.5% distributed over 7 different sarcoma subtypes. Except for one chondrosarcoma case harboring a C250T mutation, all other mutations were detected at location C228T. By far the far highest frequency of TERT promoter mutations was found in myxoid liposarcoma (MLS) (4 out of 9 cases studied, i.e., 44%). Assessment of telomere length from tumor biopsies revealed that TERT promoter-mutated MLSs had significantly fewer shortened telomeres in comparison to TERT wildtype MLSs. Based on the frequency of TERT promoter mutations and the elongated telomere length in mutated compared to wildtype MLS, we hypothesize that occurrence of TERT promoter mutations has a pivotal role in the disease progression as a secondary genetic event at a time when tumor cells face the need for telomere elongation to allow further proliferation.

Highlights

Telomeres are repetitive DNA sequences protecting the ends of chromosomes
Telomere shortening can be counteracted by the expression of telomerase (TERT), an enzyme that canelongate telomeres [3,4] a phenomenon that can be used therapeutically in vivo [5]
Previous studies showed that tumor cells mostly maintain their telomere length by increased telomerase expression [7] and rarely by a mechanism called alternative lengthening of telomere (ALT) [8]

Summary

Introduction

Telomeres shorten with each cell division, and telomere length (TL) limits the replicative capacity of a cell once telomeres become critically short [1,2]. Telomere shortening can be counteracted by the expression of telomerase (TERT), an enzyme that can (re-)elongate telomeres [3,4] a phenomenon that can be used therapeutically in vivo [5]. One of the hallmarks of cancer is unlimited cell division [6]. Previous studies showed that tumor cells mostly maintain their telomere length by increased telomerase expression [7] and rarely by a mechanism called alternative lengthening of telomere (ALT) [8]. The exact mechanism how tumor cells increase telomerase activity is incompletely understood and varies between the different tumor entities [9]

Objectives

Methods

Results