We present a rare case of a patient with gliosarcoma, a variant of glioblastoma multiforme (GBM), who developed two recurrences and extracranial bony metastases. A 37 year old woman was diagnosed with IDH wild-type gliosarcoma in the frontal lobe, treated with gross macroscopic surgical complete resection followed by concurrent radiotherapy with temozolomide. Five months later she developed an extra-axial recurrence in the left frontal lobe, outside the initial radiotherapy field and was treated with further surgery and radiotherapy. A further six months later she developed a second left frontal recurrence, treated again with surgery and radiotherapy. Another six weeks later, she had further recurrence in the brain and biopsy confirmed bony metastases. After molecular profiling revealed RAD51, FANCE and CDK12 biallelic loss, she was enrolled on a clinical trial of anti-PD-1 and PARP inhibitor combination therapy, but died several weeks later due to progression of disease.
In order to understand the clonal relationships between the four tumor instances and the origin of the metastasis, whole genome sequencing of the three intracranial tumors and the iliac bone tumor was performed. The tumors displayed a large number of mutations and copy number alterations, including shared mutations in TP53, NF1, and RB1 and deletions in CDKN2A. Whole genome doubling was identified in the first recurrence and extracranial metastasis. The patient was found to have 13 germline variants associated with risk of development of glioma that likely contributed to the observed genomic instability. Clonal phylogeny of the metastatic to intracranial tumors highlighted a high similarity in molecular profile, but contrasting evidence regarding the origin of the metastasis. The metastatic tumor was most similar to the second recurrence with respect to mutational signatures, but most similar to the first recurrence with respect to copy number profile. Results of subclonal reconstruction suggested parallel evolution of the recurrent tumors, and that the metastatic tumor was largely derived from the first recurrence. This is the first analysis of clonal evolution of extracranial metastasis in gliosarcoma and highlights alterations driving aggressive GBM progression.