Multiregion sequencing reveals the genetic heterogeneity and evolutionary history of osteosarcoma and matched pulmonary metastases

Osteosarcoma (OS) is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors (PT) and corresponding pulmonary metastatic tumors (MT) by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 OS patients. MT exhibited a significantly higher mutational burden and genomic instability compared to PT, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in MT. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of OS during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant inter-tumoral rather than intra-tumoral heterogeneity between PT and MT. Mutated genes were enriched in the PI3K-Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, MT showed improved immunogenicity including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding PT. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic OS, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis.

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