Telomere activity is associated with malignant potential in neoplasia (1). The ability to maintain telomere length is a typical feature in neoplasia and previous studies have revealed the robust expression of telomerase reverse transcriptase (TERT) in numerous human malignancies (2,3). Recurrent hot-spot mutations in the TERT promoter were intitially reported in melanoma (4,5) and subsequently in various tumor types, including primary nervous system tumors (6). Two hot-spot mutations, C228T and C250T, create novel binding sites for E-twenty-six (ETS) transcription factors, resulting in a maximum 4- to 5-fold increase in the induction of the TERT gene (4,5). Previous studies also demonstrated that TERT promoter mutations occur in ~50% of SFTs of central nervous system (CNS) origin (6). However, with the exception of myxoid liposarcomas (MLSs), TERT promoter mutations are relatively rare in soft tissue sarcomas, including SFTs (7). Our previous study reported that TERT promoter mutations are associated with poor clinical outcomes in SFT in Japanese individuals (8). However, the tumor site-specific frequency of TERT promoter mutations in our SFT cases (8) appeared to be different from previously reported values (6,7). These findings prompted the present study to elucidate the potential role of ethnic background in the possibly different frequencies of TERT promoter mutations in bone and soft tissue sarcomas.

In the present study, TERT promoter mutations were examined in 180 cases of bone and soft tissue sarcomas to elucidate its frequency in Japanese patients. It was demonstrated that TERT promoter mutation rates in MLSs of Japanese patients were lower compared with the reported values in German patients.

TERT promoter region mutations were identified in 10 cases [5 SFTs, 3 MLSs (Fig. 1), 1 pleomorphic sarcoma and 1 malignant granular cell tumor]. These mutations were confirmed as tumor-specific mutations. The clinicopathological data of cases with TERT promoter mutations are summarized in Table II. All mutations were C228T. The frequencies of TERT promoter mutation in MLS and pleomorphic undifferentiated sarcoma were 23.1 (3/13) and 5% (1/20), respectively. It was demonstrated that 2/3 MLSs with a TERT promoter mutation contained areas with a round-cell component. It was recently reported that TERT promoter mutations were associated with an adverse clinical course in SFTs (8), therefore, the prognostic impact of TERT promoter mutations in these tumors was also assessed. However, 4/5 patients with TERT-mutated tumors experienced no local recurrence or distant metastasis. Only 1 patient with TERT-mutated pleomorphic sarcoma experienced lung metastasis 46 months following the wide resection of the tumor and subsequently underwent a resection of the metastasized tumor. This patient survived and currently exhibits no evidence of the disease. Furthermore, TERT promoter mutations were detected in 1/2 patients with malignant granular cell tumor, although it was not observed in any of 5 granular cell tumors.

Other mutations neighboring the hot-spots were also noted in 3 cases, C229T in a case of synovial sarcoma, C230T in a case of myxofibrosarcoma and C232T in a case of Ewing/primitive neuroectodermal tumor, however, these mutations generated no consensus binding sites for ETS transcription factors within the TERT promoter region (10).

Telomeres are extended by the protein complex, telomerase, in which the enzyme TERT exerts a pivotal role (11). TERT promoter hot-spot mutations recently emerged as an underlying mechanism of TERT upregulation in certain human cancer types. In SFTs of the CNS, TERT promoter mutations were identified in 50% of cases (6). However, in our previous study, TERT promoter mutations were detected in 5/40 SFTs (12.5%, 0/6 of CNS origin, 2/25 of pleural/lung origin and 3/9 of soft tissue origin (8). However, another previous study reported that TERT promoter mutations were observed in 4/31 (13%) SFTs of soft tissue origin (7). These findings appear to be at odds and prompted the present study to investigate if a difference in ethnic background may contribute to this discrepancy. In the present study, a TERT promoter mutation in MLS was detected in 3/13 cases (23.1%), which is lower compared with a previously reported value of 74% in this tumor type (7). The sensitivity of the examination may affect the lower frequency of TERT promoter mutation, however, the present study attempted to enrich the quantities of tumor cells during DNA isolation. These findings supported the present hypothesis that ethnic differences may affect the frequency of TERT promoter mutations.

In the present study, 2/3 MLSs with TERT promoter mutations contained a round-cell component, however, there was no association between TERT promoter mutation and the presence of a round-cell component, consistent with previous findings (7).

Lipoblastoma is a benign lipogenic tumor arising in infants and younger children. The histology of lipoblastoma overlaps with other lipomatous tumors, including MLSs, therefore, the frequency of TERT promoter mutations was assessed in lipoblastomas. However, 0/3 cases of this tumor type harbored a TERT promoter mutation.

Granular cell tumor is a benign Schwann cell lesion and typically occurs in the skin and subcutis. The clinical and morphological criteria for malignant granular cell tumor is well described (12). In the present study, 2 cases of malignant granular cell tumors were included. The clinical course in one was previously reported in detail (13), although it was the other case, which harbored the TERT promoter mutation. Genetic alterations in malignant granular cell tumors remain to be described in detail, however, it has been reported that a malignant granular cell tumor is characterized by a gain of chromosome 10 and a loss of p16 (14). Another previous report shows that malignant granular cell tumors share certain cytogenetic abnormalities with malignant peripheral nerve sheath tumors (MPNSTs), leading to the hypothesis that they may represent histogenetically associated lesions (15). The present study identified a TERT promoter mutation in 1/2 malignant granular cell tumor cases, however, not in a sporadic MPNST case. A previous study demonstrated that the TERT promoter mutation is also rare in sporadic MPNSTs and absent in neurofibromatosis type 1-associated MPNSTs (16), although another previous study revealed that TERT promoter hot-spot mutations were observed in 6% of MPNSTs (7). The present study cannot comment on the hypothesis of histogenetic similarity between malignant granular cell tumors and MPNSTs, since the present study included only a few cases of these tumor types. However, although malignant granular cell tumors are relatively rare, it is of interest to further investigate the frequency of TERT promoter mutations in malignant granular cell tumors to elucidate the association between TERT promoter mutations and the malignant behavior of this tumor. TERT promoter mutations in this tumor type may be in part driven by its presence in the dermal or subcutaneous localization, since this type of C to T alteration is a ultraviolet signature mutation, and TERT promoter mutations are frequently observed in atypical fibroxanthomas and pleomorphic dermal sarcomas (17).

In conclusion, the present study revealed the first case, to the best of our knowledge, of malignant granular cell tumor with a TERT promoter mutation and demonstrated that the frequency of TERT promoter mutations in MLSs of Japanese patients is lower compared with that reported in German patients.