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Int J Cancer. 2018 Sep 1;143(5):1134-1142. doi: 10.1002/ijc.31389. Epub 2018 May 13.

Genetic and clonal dissection of osteosarcoma progression and lung metastasis.

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Department of Musculoskeletal Oncology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
Department of Musculoskeletal Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.
Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Ontario, Canada.
Department of Pathology, University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Department of Orthopaedics, the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China.
Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China.
Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
Department of Pathology, the first Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Orthopaedics and Traumatology, University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Department of Anatomic Pathology, Centro Hospitalar Conde de Sao Januario, Macau, China.
School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.


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.


KEAP1; PTEN; clonal evolution; metastasis; osteosarcoma

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