Prevalence Of Telomerase Reverse Transcriptase Promoter Mutations Research Articles

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

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.

Melanomas of unknown primary frequently harbor TERT-promoter mutations

Commonly, in patients with melanoma metastases of an unknown primary tumor (MUP), an extensive search for the primary tumor is carried out. Recently, highly recurrent telomerase reverse transcriptase (TERT)-promoter mutations were found in malignant melanomas, which may function as driver mutations of skin cancer. The aim of this study was to test the hypothesis that MUP and mucosal melanomas harbor different prevalences of TERT-promoter mutations. Thirty-nine patients with MUP and 53 patients with mucosal melanomas were retrieved. In total, 152 paraffin samples of 92 patients were analyzed, and in 38 patients, multiple samples were tested. Mutational analysis of the TERT-promoter, BRAF, NRAS, and KIT genes was carried out. In total, 92 patients were eligible for mutational analysis. TERT-promoter mutations were found in 33 patients (35.9%): chr5, 1,295,228 C>T (18 patients); chr5, 1,295,250 C>T (11 patients); chr5, 1,295,228-229 CC>TT (three patients); chr5, 1,295,242-243 CC>TT (one patient). The mutations were significantly more prevalent in MUP [26 (66.7%)] than in mucosal melanomas [seven patients (13.2%); P<0.001]. In MUP, BRAF mutations were found in 46.2% of patients (18 patients) and NRAS mutations in 28.2% of patients (11 patients). In mucosal melanoma, NRAS mutations were found in 18.9% of patients (10), and BRAF and KIT mutations in 7.5% of patients (four patients), respectively. The prevalence of TERT-promoter mutations was associated with the patient's sex [23 (51.1%) men, 10 (21.3%) women; P=0.004]. No significant correlation was found between TERT-mutation and patient survival. The TERT-promoter genotype of MUP points toward a cutaneous and not mucosal origin. The significant sex differences merit further attention in having putative therapeutic implications.