Genetic and clonal dissection of osteosarcoma progression and lung metastasis

Osteosarcoma is a primary malignant bone tumor that has a high potential to metastasize to lungs. Little is known about the mechanisms underlying the dissemination of OS cancer cells to lungs. We performed whole exome sequencing of 13 OS primary tumors, with matched lung metastases and normal tissues. Phylogenetic analyses revealed that lung metastatic tumors often harbor clones that are nonexistent or rare in the matched primary OS tumors. Spatially and temporally separated lung metastases were from parallel seeding events with a polyphyletic pattern. Loss of TP53 or RB1 is among the early events during OS tumorigenesis, while loss of PTEN is involved at the later stages associated with lung metastases. Finally, KEAP1 was identified as a novel biomarker for increased metastatic risk. Patients whose primary tumors harbored KEAP1 amplification have significantly poorer lung‐metastasis free survival. This finding was validated in two independent datasets. Further, in vitro experiments exhibited that KEAP1 depletion suppressed the invasion of OS cells. Our findings uncover the patterns of clonal evolution during OS progression and highlight KEAP1 as a novel candidate associated with the risk of lung metastasis in OS patients. What's new? The spread of cancer cells to the lungs in osteosarcoma is difficult to control and can fuel further progression of the disease. Little is known, however, about the mechanisms behind lung metastasis in osteosarcoma. Here, comprehensive whole exome sequencing comparing genetic alterations between primary and metastatic osteosarcomas shows that metastatic tumors harbor clones that are unique from those of primary tumors. Specific genetic events were identified in association with tumor progression. In particular, KEAP1 amplification was associated with significantly worse lung metastasis‐free survival, making it a potentially valuable biomarker for increased metastatic risk in osteosarcoma patients.