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BACKGROUND: Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to osteosarcoma at the second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation. METHODS: Tumor samples were collected at all 3 stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by the maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results. RESULTS: The glioblastoma tumor from this patient possessed mixed features of all 3 TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced transforming growth factor-β (TGF-β) and bone morphogenic protein signaling was associated with tumor transformation. Regulatory network analysis revealed that TGF-β family signaling committed the lineage tumor to osteogenesis by stimulating the expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation. CONCLUSIONS: This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.

In this study, we used a recently developed causal methodology, called Probabilistic Easy Variational Causal Effect (PEACE), to distinguish gliosarcoma (GSM) from glioblastoma (GBM). Our approach uses a causal metric which combines Probabilistic Easy Variational Causal Effect (PEACE) with the XGBoost, or eXtreme Gradient Boosting, algorithm. Unlike prior research, which often relied on statistical models to reduce dataset dimensions before causal analysis, our approach uses the complete dataset with PEACE and the XGBoost algorithm. PEACE provides a comprehensive measurement of direct causal effects, applicable to both continuous and discrete variables. Our method provides both positive and negative versions of PEACE together with their averages to calculate the positive and negative causal effects of the radiomic features on the variable representing the type of tumor (GSM or GBM). In our model, PEACE and its variations are equipped with a degree d which varies from 0 to 1 and it reflects the importance of the rarity and frequency of the events. By using PEACE with XGBoost, we achieved a detailed and nuanced understanding of the causal relationships within the dataset features, facilitating accurate differentiation between GSM and GBM. To assess the XGBoost model, we used cross-validation and obtained a mean accuracy of 83% and an average model MSE of 0.130. This performance is notable given the high number of columns and low number of rows (code on GitHub). [ABSTRACT FROM AUTHOR]

Gliosarcoma is a rare subtype of glioblastoma (GBM) with a shorter medical history and a worse prognosis compared to other Grade 4 gliomas. Most gliosarcomas are sporadic, but it is undeniable that a small percentage are linked to germline mutations and several inherited cancer susceptibility syndromes, including Lynch Syndrome (LS). The authors present a case of a primary mismatch repair-deficient gliosarcoma in LS. A 54-year-old Chinese male patient was admitted to the hospital with a history of facial asymmetry for over 1 month and right temporo-occipital pain for 5 days. Head MRI revealed a complex mass lesion in the right frontoparietal region, consisting of cystic and solid components. The patient's history of colon malignancy and family history of rectal carcinoma were noteworthy. Postoperative pathology indicated the presence of gliosarcoma with high-frequency microsatellite instability (MSI-H) and mismatch repair deficiency (MMRD). Further genetic testing results confirmed a germline heterozygous mutation in MSH2, which is considered the gold standard for diagnosing LS. This case report enriches the existing literature on germline MSH2 mutations and gliosarcomas. It highlights the importance for neurosurgeons to consider possible hereditary disorders when treating patients with a history of concurrent tumors outside the nervous system. Genetic testing is crucial for further identification of such disorders. [ABSTRACT FROM AUTHOR]