(P 236) APOBEC MUTAGENESIS IN OSTEOSARCOMA DEVELOPMENT, PROGRESSION AND RESPONSE TO THERAPY

Objective: Osteosarcoma (OS) is the most common bone tumor in humans. Every year around 800-1000 cases develop in the US. OS most commonly occurs in teens and young adults with a second incidence peak in adults aged 60+. OS frequently and quickly metastasizes to the lungs. Standard combination chemotherapy uses methotrexate, Adriamycin and platinum agents (MAP therapy). In combination with surgical resection, MAP therapy has increased five-year survival from 15-20% to over 50%. However, many patients develop therapy resistance and metastasis. OS is generally immunologically cold and targeted therapies have thus far failed. While nearly all OS tumors carry TP53 mutations, there are few clear druggable genetic drivers to target. OS is characterized by massive genomic instability with many chromosomal abnormalities, but the sources of OS genomic instability are incompletely understood. APOBEC3 enzymes are cytidine deaminases that have been shown to be involved in mutating the genomes of solid tumors through a specific and context dependent mutation signature.

Methods: We have performed bioinformatic analysis of human DNA whole exome and RNA sequencing data and preliminary mouse whole genome sequencing data.

Results: The Pan Cancer Atlas Whole Genome sequencing study has observed that some bone tumors also show APOBEC mutation signature. Here, we show that APOBEC3B expression levels and its mutation signatures correlate in an OS data set. Increased APOBEC3B levels in TARGET OS dataset shows a significant survival advantage. In other work, we have shown that APOBEC3B expression is associated with an enhanced response to platinum chemotherapy.

Conclusion: We suggest a similar synthetic lethality for APOBEC3B+ OS treated with platinum therapy. This information may help stratify OS patients. Secondly, APOBEC3B-induced mutations may include neoantigens recognizable by a nascent immune response that could be enhanced by checkpoint blockade.