Validation of a novel risk score to predict early and late recurrence in solitary fibrous tumour.

BACKGROUND: Current risk models in solitary fibrous tumour (SFT) were developed using cohorts with short follow-up and cannot reliably identify low-risk patients. We recently developed a novel risk model (G-score) to account for both early and late recurrences. Here, we aimed to validate the G-score in a large international cohort with long-term follow-up. METHODS: Data were collected from nine sarcoma referral centres worldwide. Recurrence-free interval (RFi) was the primary endpoint. RESULTS: The cohort comprised 318 patients with localised extrameningeal SFTs. Disease recurrence occurred in 96 patients (33%). The estimated 5-year RFi rate was 72%, and the 10-year RFi rate was 52%. G-score precisely predicted recurrence risk with estimated 10-year RFi rate of 84% in low risk, 54% in intermediate risk and 36% in high risk (p < 0.001; C-index 0.691). The mDemicco (p < 0.001; C-index 0.749) and SalasOS (p < 0.001; C-index 0.674) models also predicted RFi but identified low-risk patients less accurate with 10-year RFi rates of 72% and 70%, respectively. CONCLUSIONS: G-score is a highly significant predictor of early and late recurrence in SFT and is superior to other models to predict patients at low risk of relapse. A less intensive follow-up schedule could be considered for patients at low recurrence risk according to G-score.

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.

Molecular Profiling Defines Three Subtypes of Synovial Sarcoma.

Synovial Sarcomas (SS) are characterized by the presence of the SS18::SSX fusion gene, which protein product induce chromatin changes through remodeling of the BAF complex. To elucidate the genomic events that drive phenotypic diversity in SS, we performed RNA and targeted DNA sequencing on 91 tumors from 55 patients. Our results were verified by proteomic analysis, public gene expression cohorts and single-cell RNA sequencing. Transcriptome profiling identified three distinct SS subtypes resembling the known histological subtypes: SS subtype I and was characterized by hyperproliferation, evasion of immune detection and a poor prognosis. SS subtype II and was dominated by a vascular-stromal component and had a significantly better outcome. SS Subtype III was characterized by biphasic differentiation, increased genomic complexity and immune suppression mediated by checkpoint inhibition, and poor prognosis despite good responses to neoadjuvant therapy. Chromosomal abnormalities were an independent significant risk factor for metastasis. KRT8 was identified as a key component for epithelial differentiation in biphasic tumors, potentially controlled by OVOL1 regulation. Our findings explain the histological grounds for SS classification and indicate that a significantly larger proportion of patients have high risk tumors (corresponding to SS subtype I) than previously believed.

Transcriptome profiling of Ewing sarcomas - treatment resistance pathways and IGF-dependency.

Ewing sarcomas (ESs) are aggressive sarcomas driven by EWS fusion genes. We sought to investigate whether whole-transcriptome sequencing (RNA-seq) could be used to detect patterns associated with chemotherapy response or tumor progression after first-line treatment. Transcriptome sequencing (RNA-seq) of 13 ES cases was performed. Among the differentially expressed pathways, we identified IGF2 expression as a potential driver of chemotherapy response and progression. We investigated the effect of IGF2 on proliferation, radioresistance, apoptosis, and the transcriptome pattern in four ES cell lines and the effect of IGF2 expression in a validation series of 14 patients. Transcriptome analysis identified differentially expressed genes (adj. P < 0.005) and pathways associated with chemotherapy response (285 genes), short overall survival (662 genes), and progression after treatment (447 genes). Imprinting independent promoter P3-mediated IGF2 expression was identified in a subset of cases with aggressive clinical course. In ES cell lines, IGF2 induced proliferation, but promoted radioresistance only in CADO cells. High IGF2 expression was also significantly associated with shorter overall survival in patients with ES. Transcriptome analysis of the clinical samples and the cell lines revealed an IGF-dependent signature, potentially related to a stem cell-like phenotype. Transcriptome analysis is a potentially powerful complementary tool to predict the clinical behavior of ES and may be utilized for clinical trial stratification strategies and personalized oncology. Certain gene signatures, for example, IGF-related pathways, are coupled to biological functions that could be of clinical importance. Finally, our results indicate that IGF inhibition may be successful as a first-line therapy in conjunction with conventional radiochemotherapy for a subset of patients.

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.