Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma.
Gian Luca NegriBruno M GrandeAlberto DelaidelliAmal M El-NaggarDawn R CochraneChing C LauTimothy J TricheRichard A MooreSteven Jm JonesAlexandre MontpetitMarco A MarraDavid MalkinRyan D MorinPoul H SorensenPublished in: The Journal of pathology (2019)
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.
Keyphrases
- copy number
- mitochondrial dna
- poor prognosis
- genome wide
- dna damage response
- squamous cell carcinoma
- small cell lung cancer
- single cell
- dna methylation
- dna repair
- long non coding rna
- newly diagnosed
- prognostic factors
- childhood cancer
- dna damage
- lymph node metastasis
- young adults
- patient reported outcomes
- body composition
- bone mineral density
- soft tissue
- genetic diversity