BRCA-like phenotype constitutes hallmark of osteosarcoma

Background: Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which limits treatment options in patients who do not respond to standard chemotherapy. Methods: We sequenced 104 exomes and low-coverage genomes from 14 time-series consisting of chemotherapy-naive biopsies, resection specimens, locally recurring tumours and/or distant metastases. We then identified cancer driver mutations, signatures of mutation processes and reconciled clonal structures of tumours with phylogenetic trees, thus building and evolutionary history of each tumour. Where possible, we searched for the evidence of selection acting on the tumours and molecular hallmarks that could be therapeutically exploited. Results: Interrogating genomic data from time series, we identified pathogenic mutations in at least 10 cancer genes, but there was no universal cancer driver event present in the majority of tumours at any given time point. However, u003e80% of osteosarcomas exhibited specific combination of single-base substitutions, LOH and large-scale genome instability characteristic of BRCA1/2-deficient tumours. In osteosarcoma, BRCAness developed recurrently through independent BRCA1/2 mutations and mutations in their binding partners such as PALB2 or CHEK2. We therefore investigated the sensitivity of a panel of osteosarcoma cell lines to the poly(ADP)-ribose polymerase inhibitor talazoparib. In combination with temozolomide, talazoparib led to the to good response of osteosarcoma cell lines, activation of BAX and BAK, loss of mitochondrial membrane potential, DNA fragmentation and caspase-dependent cell death. Conclusion: The acquisition of a BRCA-like phenotype in osteosarcoma has implications for the development of novel treatment strategies using PARP inhibitors alone, or together with standard chemotherapy. Citation Format: Michal Kovac, Sebastian Ribi, Claudia Blattmann, Michaela Nathrath, Daniel Baumhoer. BRCA-like phenotype constitutes hallmark of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1634.