Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma

J Pathol. 2019 Nov;249(3):319-331. doi: 10.1002/path.5319. Epub 2019 Aug 28.


Despite being the most common childhood bone tumor, the genomic characterization of osteosarcoma remains incomplete. In particular, very few osteosarcoma metastases have been sequenced to date, critical to better understand mechanisms of progression and evolution in this tumor. We performed an integrated whole genome and exome sequencing analysis of paired primary and metastatic pediatric osteosarcoma specimens to identify recurrent genomic alterations. Sequencing of 13 osteosarcoma patients including 13 primary, 10 metastatic, and 3 locally recurring tumors revealed a highly heterogeneous mutational landscape, including cases of hypermutation and microsatellite instability positivity, but with virtually no recurrent alterations except for mutations involving the tumor suppressor genes RB1 and TP53. At the germline level, we detected alterations in multiple cancer related genes in the majority of the cohort, including those potentially disrupting DNA damage response pathways. Metastases retained only a minimal number of short variants from their corresponding primary tumors, while copy number alterations showed higher conservation. One recurrently amplified gene, KDR, was highly expressed in advanced cases and associated with poor prognosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: KDR; VEGF; childhood bone sarcomas; genome sequencing; metastasis; osteosarcoma.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Biomarkers, Tumor / genetics*
  • Bone Neoplasms / genetics*
  • Bone Neoplasms / pathology*
  • British Columbia
  • DNA Copy Number Variations
  • Female
  • Gene Amplification
  • Gene Dosage
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Microsatellite Instability
  • Mutation
  • Neoplasm Recurrence, Local / genetics*
  • Neoplasm Recurrence, Local / pathology*
  • Osteosarcoma / genetics*
  • Osteosarcoma / secondary*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Transcriptome
  • United States
  • Whole Exome Sequencing
  • Whole Genome Sequencing*


  • Biomarkers, Tumor