The clonal evolution of metastatic osteosarcoma as shaped by cisplatin treatment

Samuel W. Brady, Xiaotu Ma, Armita Bahrami, Gryte Satas, Gang Wu, Scott Newman, Michael Rusch, Daniel K. Putnam, Heather L. Mulder, Donald A. Yergeau, Michael N. Edmonson, John Easton, Ludmil B. Alexandrov, Xiang Chen, Elaine R. Mardis, Richard K. Wilson, James R. Downing, Alberto S. Pappo, Benjamin J. Raphael, Michael A. DyerJinghui Zhang

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


To investigate the genomic evolution of metastatic pediatric osteosarcoma, we performed whole-genome and targeted deep sequencing on 14 osteosarcoma metastases and two primary tumors from four patients (two to eight samples per patient). All four patients harbored ancestral (truncal) somatic variants resulting in TP53 inactivation and cell-cycle aberrations, followed by divergence into relapse-specific lineages exhibiting a cisplatin-induced mutation signature. In three of the four patients, the cisplatin signature accounted for >40% of mutations detected in the metastatic samples. Mutations potentially acquired during cisplatin treatment included NF1 missense mutations of uncertain significance in two patients and a KIT G565R activating mutation in one patient. Three of four patients demonstrated widespread ploidy differences between samples from the sample patient. Single-cell seeding of metastasis was detected in most metastatic samples. Crossseeding between metastatic sites was observed in one patient, whereas in another patient a minor clone from the primary tumor seeded both metastases analyzed. These results reveal extensive clonal heterogeneity in metastatic osteosarcoma, much of which is likely cisplatin-induced. Implications: The extent and consequences of chemotherapyinduced damage in pediatric cancers is unknown. We found that cisplatin treatment can potentially double the mutational burden in osteosarcoma, which has implications for optimizing therapy for recurrent, chemotherapy-resistant disease.

Original languageEnglish (US)
Pages (from-to)895-906
Number of pages12
JournalMolecular Cancer Research
Issue number4
StatePublished - 2019

All Science Journal Classification (ASJC) codes

  • General Medicine


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