TERT promoter hotspot mutations are recurrent in myxoid liposarcomas but rare in other soft tissue sarcoma entities.

Christian Koelsche,Peter Schirmacher,Roland Penzel,Ingo Alldinger,Thomas Schmitt,Nina Waldburger,Burkhard Lehner,Regine Brandt,Gerlinde Egerer,Eva Wardelmann,Gunhild Mechtersheimer,Andreas Von Deimling,Wolfgang Hartmann,Marcus Renner

doi:10.1186/1756-9966-33-33

Abstract

BackgroundRecently, recurrent point mutations in the telomerase reverse transcriptase (TERT) promoter region have been found in many human cancers, leading to a new transcription factor binding site, increased induction of TERT and subsequently to telomere maintenance. We determined the prevalence of TERT promoter mutations in soft tissue sarcomas of 341 patients comprising 16 entities and in 16 sarcoma cell lines covering 7 different soft tissue sarcoma types.MethodsThe sarcoma tissue samples were collected from the archives of the Institute of Pathology, University of Heidelberg and were composed of 39 myxoid liposarcomas (MLS), 61 dedifferentiated liposarcomas, 15 pleomorphic liposarcomas, 27 leiomyosarcomas, 25 synovial sarcomas (SS), 35 malignant peripheral nerve sheath tumors (MPNST), 40 undifferentiated pleomorphic sarcomas, 17 myxofibrosarcomas, 9 low grade fibromyxoid sarcomas, 10 cases of dermatofibrosarcoma protuberans, 31 solitary fibrous tumors (SFT), 8 extraskeletal myxoid chondrosarcomas, 9 angiosarcomas, 6 alveolar soft part sarcomas, 5 clear cell sarcomas and 4 epithelioid sarcomas. Sarcoma cell lines were obtained from the raising laboratories. A 193 bp fragment of the TERT promoter region covering the hot-spot mutations C228T and C250T was amplified, and direct sequencing of the PCR products was performed.ResultsTERT promoter mutations were detected in 36/341 sarcomas. They were highly recurrent in MLS (29/39; 74%) and were in the present MLS series not associated with the phenotype (myxoid vs. round cell variant), tumor grade, tumor site and patients’ median age or gender. In the remaining cases, TERT promoter mutations were found only in 7/302 sarcoma samples and confined to SFTs (4/31; 13%), MPNSTs (2/35; 6%), and SSs (1/25; 4%). Within the collection of sarcoma cell lines examined, TERT promoter mutations were detected in two MLS and in one of three MPNST cell lines.ConclusionsTERT promoter mutations are frequent in MLSs including their round cell variants, representing the most prevalent mutation identified in this sarcoma entity to date, and in a minor fraction of SFTs, MPNSTs and SSs. The majority of sarcomas are devoid of TERT promoter hotspot mutations. These data suggest that telomere maintenance through increased expression of telomerase plays an important role in the pathogenesis especially of MLS.

Highlights

Recurrent point mutations in the telomerase reverse transcriptase (TERT) promoter region have been found in many human cancers, leading to a new transcription factor binding site, increased induction of TERT and subsequently to telomere maintenance
Sarcoma samples and clinicopathological characteristics The sarcoma tissue samples were collected at the Institute of Pathology, University of Heidelberg, and diagnoses were confirmed by three sarcoma pathologists (GM, WH and EW)
The 28 myxoid liposarcomas (MLS) carrying a C228T mutation were all positive for the FUS-DDIT3 fusion, while the C250T mutation was found in one of two MLS with an EWSR1-DDIT3 fusion transcript (Additional file 1: Table S2)

Summary

Introduction

Recurrent point mutations in the telomerase reverse transcriptase (TERT) promoter region have been found in many human cancers, leading to a new transcription factor binding site, increased induction of TERT and subsequently to telomere maintenance. We determined the prevalence of TERT promoter mutations in soft tissue sarcomas of 341 patients comprising 16 entities and in 16 sarcoma cell lines covering 7 different soft tissue sarcoma types. STS are relatively rare and constitute approximately 1–2% of all human cancers, but incidence dramatically increases with age [1,2]. The treatment of choice depends on the individual tumor type, grading and staging status. Under these circumstances, advance in personalized treatment strategies might become important with the goal to individual tumor-targeted therapies

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