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

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.

High prevalence of TERT aberrations in myxoid liposarcoma: TERT reactivation may play a crucial role in tumorigenesis

“…It exhibits the reciprocal translocation, t(12;16)(q13;p11), in approximately 95% of patients, which results in the fusion of FUS‐DDIT3, and t(12;22)(q13;q12) in nearly 5% of patients, resulting in the formation of EWSR1‐DDIT3 20,21 . Soft tissue sarcomas generally show a high frequency of ALT, while MLPS is the only exception and is known to have a high prevalence of TERT promoter ( TERT p) mutations (22.2%‐79.1%) 5,14,22‐26 . It has also been reported that 5%‐18% of patients with MLPS have ALT, 27,28 and telomerase activation and ALT are not mutually exclusive 27 .…”

Unravelling undifferentiated soft tissue sarcomas: insights from genomics

“…The increased expression of telomerase is predominantly caused by mutations of the TERT promoter 38 (Figure 4A) and, less frequently, by gene amplification or rearrangements 34,39 . Several studies have identified TERT promoter SNV mutations in different sarcomas 40–45 . TERT promoter mutations have been commonly identified in multiple subtypes, including atypical fibrous xanthoma (25 of 27 cases, 93%), pleomorphic dermal sarcoma (26 of 34 cases, 76%), myxoid liposarcoma (57 of 94 cases, 61%), and solitary fibrous tumour (38 of 176 cases, 22%).…”

“…TERT promoter mutations have been commonly identified in multiple subtypes, including atypical fibrous xanthoma (25 of 27 cases, 93%), pleomorphic dermal sarcoma (26 of 34 cases, 76%), myxoid liposarcoma (57 of 94 cases, 61%), and solitary fibrous tumour (38 of 176 cases, 22%). USTSs, on the other hand, rarely harbour TERT promoter SNV mutations (<2% of cases), 7,41,43,44 but a subset of cases show recurrent complex structural rearrangements of chromosome 5p15.33, which lies proximal to TERT (Figure 4B). 7 These 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements that transcriptionally up‐regulate telomerase in a similar manner to that seen in some neuroblastomas 7,46 .…”

Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation

“…Mutations in the TERT promoter region were identified by PCR and Sanger sequencing as described previously [31]. The detailed protocol can be found in the Supplementary Materials and methods.…”

“…TL analysis was done by a modified protocol of immunoquantitative fluorescence in situ hybridization (Q-FISH) as previously described [31][32][33][34][35]. FFPE sections of the cohort were deparaffinized and rehydrated before antigen retrieval in 10 mM citrate buffer (pH 6.0).…”