TERT promoter mutation is an objective clinical marker for disease progression in chondrosarcoma.

Chondrosarcomas are the second most common malignant bone tumor. Activating promoter mutations in telomerase reverse transcriptase (TERT) was recently described by us and others as a frequent mutation in high-grade chondrosarcoma. In this study, we investigate the prognostic significance of TERT promoter mutations in 241 chondrosarcomas from 190 patients collected over 24 years (1994-2017). The TERT promoter was sequenced after microdissection of 135 chondrosarcomas from 106 patients in addition to data from our previous cohort. The TERT promoter mutation at -124 C > T was found in 45% of all patients and was significantly associated (p > 0,001) with higher tumor grade, shorter metastasis-free survival, and disease-specific survival. Additionally, TERT promoter-mutated tumors were associated with a more aggressive metastatic pattern. Shorter survival was observed in patients with wild-type primary tumors who developed a mutated metastasis indicative of tumor progression. Primary tumor genetic heterogeneity and altering mutational status between nonsynchronous metastatic lesions suggests that chondrosarcoma is a multiclonal disease progressing through a branching evolution. Conclusion: TERT promoter mutation seems to be a central event in chondrosarcoma progression with association to metastatic disease and disease-related mortality. As an easily analyzed marker, there is future potential to utilize TERT promoter mutation status as a prognostic marker and investigate telomerase-targeted therapy in chondrosarcomas.

hTERT promoter mutations in chondrosarcomas associate with progression and disease-related mortality.

Chondrosarcomas are malignant skeletal tumors with chondroid differentiation. Prognosis is largely dependent on histological grading, which suffer from significant interobserver variability. Telomerase activity and abundant telomerase reverse transcriptase (hTERT) expression has previously been associated with chondrosarcoma grade and metastasis. We therefore analyzed the hTERT promoter in clinicopathologically well-characterized chondrosarcomas (grade 1-3) from 87 patients. Using Sanger sequencing we identified an activating -124 C > T mutation in 23 cases (26%). Promoter mutations were significantly associated with increased histological grade (8% of grade 1, 32% of grade 2 and 46% of grade 3, P = 0.002), suggesting a role in tumor progression. In four chondrosarcomas where the histopathological grade was heterogenous, the hTERT mutation was only identified in the higher-grade areas. Additionally, hTERT promoter mutations were significantly associated with worse metastasis-free survival (P = 0.018), chondrosarcoma-specific survival (P = 0.022) and older patient age (P = 0.003). These data suggest that hTERT promoter mutations are common in high grade conventional chondrosarcomas. Granted that additional studies can confirm these findings; hTERT promoter analysis could potentially serve as an adjuvant prognostic marker in routine chondrosarcoma grading. This study reinforces the rationale of telomerase targeted therapy in a subset of chondrosarcomas.

Telomerase promoter mutations and copy number alterations in solitary fibrous tumours.

AIMS: Solitary fibrous tumour (SFT) is an infrequently metastasising mesenchymal tumour defined by the NAB2-STAT6 fusion gene. Activating mutations in the telomerase reverse transcriptase (hTERT) gene promoter has been reported to associate with adverse patient outcome in SFTs. METHODS: We analysed the hTERT gene for promoter mutations and copy number alterations in 43 primary extrameningeal SFTs (9 malignant and 34 benign tumours according to WHO 2013 criteria), six local recurrences and three metastatic lesions. RESULTS: Activating -124 C>T (n=12) or -148 C>T (n=2) mutations were found in 33% of the tumours and associated with older age (P=0.006), necrosis (P=0.009), higher mitotic rate (P=0.003), nuclear atypia (P=0.002), malignant histological diagnosis (P=0.04) and worse progression-free survival (P=0.023). We also observed frequent (24%) hTERT promoter mutations in histologically benign tumours without metastasis (mean follow-up >9 years), and in 14%-18% of low-risk SFTs as determined by three risk-stratification models. Mutations were seen in 2/6 metastatic tumours and metastatic lesions. hTERT copy number gain was seen in 11/28 hTERT promoter wild-type cases. CONCLUSIONS: Activating hTERT promoter mutations associate with aggressive histopathological features, indicating a role in tumour progression. Given the comparatively high prevalence of hTERT promoter mutations in low-risk and non-metastasising lesions, further studies are required to clarify the prognostic value of hTERT promoter analysis before implementing the analysis in clinical diagnostics.