The variable genomic landscape during osteosarcoma progression: insights from a longitudinal WGS analysis

Abstract Osteosarcoma is a primary bone tumor that exhibits a complex genome characterized by gross chromosomal abnormalities. Osteosarcoma patients often develop metastatic disease, resulting in limited therapeutic options and poor survival rates. To gain knowledge on the mechanisms underlying osteosarcoma heterogeneity and metastatic process, it is important to obtain a detailed profile of the genomic alterations that accompany osteosarcoma progression. We performed WGS on multiple tissue samples from six patients with osteosarcoma, including the treatment naïve biopsy of the primary tumor, resection of the primary tumor after neoadjuvant chemotherapy, local recurrence and distant metastases. SNVs and structural variants were found to accumulate over time, contributing to an increased complexity of the genome of osteosarcoma during progression. Phylogenetic trees based on SNVs and structural variants reveal distinct evolutionary patterns between patients, including linear, neutral and branched patterns. The majority of osteosarcomas showed variable copy number profiles or gained whole genome doubling in later occurrences. Additionally, chromothripsis is not confined to a single early event, as multiple other chromothripsis events may appear in later occurrences. Together, we provide a detailed analysis of the complex genome of osteosarcomas and show that five out of six osteosarcoma genomes are highly dynamic and variable during progression.